TW202143958A - Farnesoid x receptor agonists for the treatment of disease - Google Patents
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Abstract
Description
本文中描述用於治療因利用法尼醇X受體促效劑(單獨或與其他治療劑組合)之治療而受益之病狀、疾病或病症之治療策略。Described herein are therapeutic strategies for treating conditions, diseases, or disorders that would benefit from treatment with a farnesoid X receptor agonist, alone or in combination with other therapeutic agents.
法尼醇X受體(FXR)為於肝、腸、腎及脂肪組織中表現之細胞核受體。FXR調節涉及控制膽汁酸合成及轉運、脂質代謝及葡萄糖穩態之廣泛各種標靶基因。FXR促效為許多代謝性病狀及肝病之治療方式。Farnesoid X receptor (FXR) is a nuclear receptor expressed in liver, intestine, kidney and adipose tissue. FXR regulation involves a wide variety of target genes that control bile acid synthesis and transport, lipid metabolism and glucose homeostasis. FXR potentiation is a treatment modality for many metabolic conditions and liver diseases.
於一個態樣中，本文中描述一種治療或預防個體之脂肪肝病之方法，其包括向該患有脂肪肝病之個體投與化合物，該化合物為反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物，其中：該個體視情況患有糖尿病；向該個體經口投與約10 mg至約100 mg化合物1；及化合物1或其醫藥上可接受之鹽或溶劑化物視情況與至少一種附加治療劑投與。於一些實施例中，該脂肪肝病為非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)或酒精性脂肪性肝炎(ASH)。於一些實施例中，治療脂肪肝病包括肝脂肪減少、肝組織學改善、肝血液測試改善、膽汁鬱積性搔癢改善或其組合。於一些實施例中，治療脂肪肝病包括增加血清FGF-19含量、降低血清7α-羥基-4-膽烯-3-酮(C4)含量、降低血清膽汁酸含量或其組合。於一些實施例中，該個體患有糖尿病且該糖尿病為2型糖尿病。於一些實施例中，該至少一種附加治療劑為血管收縮素2型受體促效劑、酮己糖激酶(KHK)抑制劑、粒線體解偶聯劑或質子載體、鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、二氫神經醯胺去飽和酶1 (DES-1)抑制劑、整合素aVb1抑制劑、整合素aVb6抑制劑、類NOD受體蛋白3 (NLRP3)抑制劑、親環素抑制劑、類升糖素胜肽-1 (GLP-1)促效劑、17-β-羥基類固醇脫氫酶13型(17b-HSD 13型)抑制劑、甲狀腺激素受體β (THR-β)促效劑或其組合。於一些實施例中，該至少一種附加治療劑為鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、類升糖素胜肽-1 (GLP-1)促效劑或其組合。In one aspect, described herein is a method of treating or preventing fatty liver disease in an individual comprising administering to the individual having fatty liver disease a compound that is trans- N- (3-(1-cyclopropane) yl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cycle Hexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof, wherein: the subject optionally has diabetes; about 10 mg to about 100 mg of
於一些實施例中，化合物1或其醫藥上可接受之鹽以口服溶液、口服懸浮液、粉末、丸劑、錠劑或膠囊之形式向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該個體投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽按照滴定時程表向該個體經口投與。於一些實施例中，該滴定時程表包括每日投與約50 mg化合物1或其醫藥上可接受之鹽持續一段時間，接著每日投與約80 mg化合物1或其醫藥上可接受之鹽。於一些實施例中，該時間段包括1天、約1週、約2週、約3週、約4週、約5週、約6週、約7週、約8週、約9週、約10週、約11週或約12週。In some embodiments,
於另一態樣中，本文中描述一種評價於患有脂肪肝病之個體中對利用法尼醇X受體(FXR)促效劑治療之臨床反應的方法，其包括： (a)在開始利用法尼醇X受體(FXR)促效劑治療之前，評估該患有脂肪肝病之個體之該肝脂肪含量(LFC)； (b)以初始每日劑量向該患有脂肪肝病之個體投與法尼醇X受體(FXR)促效劑持續初始時間段； (c)再次評估該患有脂肪肝病之個體之該肝脂肪含量(LFC)；及 (d)若該步驟(a)中之LFC高於該步驟(b)之LFC，則繼續每日投與該FXR促效劑或若該步驟(b)中之LFC與該步驟(a)中之LFC實質上相似，則停藥每日投與該FXR促效劑之治療。In another aspect, described herein is a method of evaluating clinical response to treatment with a farnesoid X receptor (FXR) agonist in an individual with fatty liver disease, comprising: (a) assessing the liver fat content (LFC) in the subject with fatty liver disease prior to initiating treatment with a farnesoid X receptor (FXR) agonist; (b) administering to the subject with fatty liver disease a farnesoid X receptor (FXR) agonist at an initial daily dose for an initial period of time; (c) reassess the liver fat content (LFC) of the individual with fatty liver disease; and (d) if the LFC in step (a) is higher than the LFC in step (b), continue daily administration of the FXR agonist or if the LFC in step (b) is the same as in step (a) If the LFC is substantially similar, the daily administration of the FXR agonist is discontinued.
於一些實施例中，該初始時間段為約2週、約3週或約4週。於一些實施例中，該初始時間段為約4週。In some embodiments, the initial period of time is about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the initial period of time is about 4 weeks.
於一些實施例中，該FXR促效劑按照滴定時程表向該個體投與。於一些實施例中，該滴定時程表包括以下之一或多個週期：以第一每日量投與該FXR促效劑持續約1週之時間，接著：以增加之每日量投與該FXR促效劑或以減少之每日量投與該FXR促效劑，視情況接著增加投與之該FXR促效劑之該每日量。於一些實施例中，該滴定時程表包括以下之一或多個週期：以第一每日量投與該FXR促效劑持續約1週之時間，接著以增加之每日量投與該FXR促效劑。於一些實施例中，該滴定時程表之該第一每日量小於步驟(b)之該初始每日量。於一些實施例中，重複該投與週期。於一些實施例中，該方法進一步包括： (i)於利用該法尼醇X受體(FXR)促效劑治療約12週後，評估該患有脂肪肝病之個體之該肝脂肪含量(LFC)； (ii)若步驟(c)與步驟(i)之間之LFC之該相對變化小於約10%，則調整該FXR促效劑之該每日劑量。In some embodiments, the FXR agonist is administered to the subject according to a titration schedule. In some embodiments, the titration schedule includes one or more cycles of: administering the FXR agonist in a first daily amount for a period of about 1 week, followed by: administering an increasing daily amount The FXR agonist is either administered in a decreasing daily amount, optionally followed by an increase in the daily amount of the FXR agonist administered. In some embodiments, the titration schedule includes one or more cycles of administering the FXR agonist in a first daily amount for a period of about 1 week, followed by administration of the FXR agonist in an increasing daily amount FXR agonist. In some embodiments, the first daily amount of the titration schedule is less than the initial daily amount of step (b). In some embodiments, the dosing cycle is repeated. In some embodiments, the method further includes: (i) assessing the liver fat content (LFC) in the subject with fatty liver disease after about 12 weeks of treatment with the farnesoid X receptor (FXR) agonist; (ii) If the relative change in LFC between step (c) and step (i) is less than about 10%, then adjust the daily dose of the FXR agonist.
於一些實施例中，調整該FXR促效劑之該每日劑量包括增加該FXR促效劑之該每日劑量。於一些實施例中，調整該FXR促效劑之該每日劑量包括減少該FXR促效劑之該每日劑量。於一些實施例中，調整該FXR促效劑之該每日劑量包括若步驟(c)與步驟(i)之間之LFC之相對變化小於10%，則增加該FXR促效劑之該每日劑量。於一些實施例中，調整該FXR促效劑之該每日劑量包括若步驟(c)與步驟(i)之間之LFC之相對變化小於20%，則增加該FXR促效劑之該每日劑量。於一些實施例中，調整該FXR促效劑之該每日劑量包括利用滴定時程表增加該每日劑量。於一些實施例中，該FXR促效劑為反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物。於一些實施例中，步驟(b)中之化合物1之初始每日劑量為約50 mg。於一些實施例中，調整該FXR促效劑之該每日劑量包括若步驟(c)與步驟(i)之間之LFC之相對變化小於10%，則自約50 mg至約80 mg增加化合物1之每日劑量。於一些實施例中，利用磁共振成像-質子密度脂肪分數(MRI-PDFF)來評估該LFC。In some embodiments, adjusting the daily dose of the FXR agonist comprises increasing the daily dose of the FXR agonist. In some embodiments, adjusting the daily dose of the FXR agonist comprises reducing the daily dose of the FXR agonist. In some embodiments, adjusting the daily dose of the FXR agonist comprises increasing the daily dose of the FXR agonist if the relative change in LFC between step (c) and step (i) is less than 10%. dose. In some embodiments, adjusting the daily dose of the FXR agonist comprises increasing the daily dose of the FXR agonist if the relative change in LFC between step (c) and step (i) is less than 20%. dose. In some embodiments, adjusting the daily dose of the FXR agonist comprises increasing the daily dose using a titration schedule. In some embodiments, the FXR agonist is trans- N- (3-(1-cyclopropyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans Formula- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the initial daily dose of
於另一態樣中，本文中描述一種治療肝臟疾病或病狀、脂質疾病或病症、代謝炎症介導之疾病或病症、胃腸疾病或病狀、腎疾病或病狀、癌症或其組合之方法，其包括向有需要個體經口投與約10 mg至約160 mg為反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)之化合物，或其醫藥上可接受之鹽或溶劑化物；其中化合物1或其醫藥上可接受之鹽或溶劑化物。於一些實施例中，治療該肝臟疾病或病狀、脂質疾病或病症、代謝炎症介導之疾病或病症、胃腸疾病或病狀、腎疾病或病狀、癌症或其組合包括增加血清FGF-19含量、降低血清7α-羥基-4-膽烯-3-酮(C4)含量、降低血清膽汁酸含量或其組合。於一些實施例中，向有需要個體經口投與約30 mg、約40 mg、50 mg、約60 mg、約70 mg、約80 mg、約90 mg、約100 mg、約110 mg、約120 mg、約130 mg、約140 mg、約150 mg或約160 mg化合物1。In another aspect, described herein is a method of treating a liver disease or condition, a lipid disease or condition, a metabolic inflammation-mediated disease or condition, a gastrointestinal disease or condition, a renal disease or condition, cancer, or a combination thereof , which comprises orally administering to a subject in need thereof from about 10 mg to about 160 mg of trans- N- (3-(1-cyclopropyl- 1H -pyrazol-4-yl)phenyl)-4- A compound of hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (Compound 1), or a pharmaceutically acceptable compound thereof The salt or solvate; wherein
於一些實施例中，該肝臟疾病或病狀為脂肪性肝炎、膽管炎、脂肪肝病、膽汁鬱積、肝硬化、纖維化肝病、肝發炎、原發性膽汁性膽管炎、膽道閉鎖、阿拉吉歐症候群、IFALD (腸衰竭相關聯之肝病)、胃腸外營養相關聯之肝病(PNALD)、肝炎、肝細胞癌、膽管癌或其組合。In some embodiments, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrotic liver disease, liver inflammation, primary biliary cholangitis, biliary atresia, alajic European syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof.
於一些實施例中，該脂肪性肝炎為非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)或HIV相關聯之脂肪性肝炎；膽管炎為原發性膽汁性膽管炎(PBC)或原發性硬化性膽管炎(PSC)；該脂肪肝病為非酒精性脂肪肝病(NAFLD)或酒精相關脂肪肝病；該膽汁鬱積為肝內膽汁鬱積、肝外膽汁鬱積、妊娠期肝內膽汁鬱積或進行性家族性肝內膽汁鬱積(PFIC)；該代謝炎症介導之疾病或病症為糖尿病。In some embodiments, the steatohepatitis is nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or HIV-associated steatohepatitis; the cholangitis is primary biliary cholangitis (PBC). ) or primary sclerosing cholangitis (PSC); the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or alcohol-related fatty liver disease; the cholestasis is intrahepatic cholestasis, extrahepatic cholestasis, intrahepatic bile of pregnancy Smoldering or progressive familial intrahepatic cholestasis (PFIC); the disease or condition mediated by metabolic inflammation is diabetes.
於一些實施例中，該纖維化肝病為產生自以下之纖維化肝病：非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、非酒精性脂肪肝病(NAFLD)、原發性膽汁性膽管炎(PBC)、原發性硬化性膽管炎(PSC)、C型肝炎病毒(HCV)、肝硬化、威爾森氏病(Wilson's disease)、HIV相關聯之脂肪性肝炎、HIV相關聯之肝硬化或先天性肝纖維化；該肝發炎為急性肝炎、慢性肝炎、猛爆性肝炎、病毒性肝炎、細菌性肝炎、寄生蟲性肝炎、毒物及藥物誘導之肝炎、酒精性肝炎、自體免疫性肝炎、非酒精性脂肪性肝炎(NASH)、新生兒肝炎或缺血性肝炎。In some embodiments, the fibrotic liver disease is a fibrotic liver disease resulting from nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), primary Biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatitis C virus (HCV), cirrhosis, Wilson's disease, HIV-associated steatohepatitis, HIV-related associated liver cirrhosis or congenital liver fibrosis; the liver inflammation is acute hepatitis, chronic hepatitis, fulminant hepatitis, viral hepatitis, bacterial hepatitis, parasitic hepatitis, poison and drug-induced hepatitis, alcoholic hepatitis, Autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), neonatal hepatitis or ischemic hepatitis.
於又一態樣中，本文中描述一種治療肝臟疾病或病狀、脂質疾病或病症、代謝炎症介導之疾病或病症或其組合之方法，其包括向有需要個體經口投與約10 mg至約160 mg為反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)之化合物，或其醫藥上可接受之鹽或溶劑化物；其中化合物1或其醫藥上可接受之鹽或溶劑化物。於一些實施例中，肝臟疾病或病狀為非酒精性脂肪性肝炎(NASH)；該脂質疾病或病狀為血脂異常；及該代謝炎症介導之疾病或病症為糖尿病。於一些實施例中，治療該肝臟疾病或病狀、脂質疾病或病症、代謝炎症介導之疾病或病症或其組合包括增加血清FGF-19含量、降低血清7α-羥基-4-膽烯-3-酮(C4)含量、降低血清膽汁酸含量或其組合。於一些實施例中，向有需要個體經口投與約30 mg、約40 mg、50 mg、約60 mg、約70 mg、約80 mg、約90 mg、約100 mg、約110 mg、約120 mg、約130 mg、約140 mg、約150 mg或約160 mg化合物1。In yet another aspect, described herein is a method of treating a liver disease or condition, a lipid disease or disorder, a metabolic inflammation-mediated disease or disorder, or a combination thereof, comprising orally administering about 10 mg to an individual in need thereof To about 160 mg as trans- N- (3-(1-cyclopropyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4- A compound of methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof; wherein
於一些實施例中，該胃腸疾病或病狀為壞死性小腸結腸炎、發炎性腸病(IBD)、大腸激躁症候群(IBS)、胃腸炎、輻射誘導之腸炎、假膜性結腸炎、腸炎、乳糜瀉、腸手術後發炎、移植物抗宿主疾病、膽汁酸逆流或結腸直腸癌。於一些實施例中，該發炎性腸病(IBD)為克羅恩氏病(Crohn’s disease)或潰瘍性結腸炎。於一些實施例中，該大腸激躁症候群(IBS)為大腸激躁症候群伴腹瀉(IBS-D)、大腸激躁症候群伴便秘(IBS-C)、混合型IBS (IBS-M)、未分亞型之IBS (IBS-U)或膽汁酸腹瀉(BAD)。於一些實施例中，該IBS-D係由於膽汁酸吸收不良。於一些實施例中，該胃腸疾病或病狀為結腸炎。於一些實施例中，該結腸炎為潰瘍性結腸炎、顯微鏡性結腸炎或假膜性結腸炎。於一些實施例中，該腸炎為輻射誘導之腸炎或化療誘導之腸炎；該胃腸炎為特發性胃腸炎。於一些實施例中，該胃腸疾病或病狀為伴隨胃-食道逆流疾病(GERD)之膽汁酸逆流或不伴隨GERD之膽汁酸逆流。In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, enteritis , celiac disease, inflammation after bowel surgery, graft-versus-host disease, bile acid reflux, or colorectal cancer. In some embodiments, the inflammatory bowel disease (IBD) is Crohn's disease or ulcerative colitis. In some embodiments, the irritable bowel syndrome (IBS) is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unspecified Subtypes of IBS (IBS-U) or bile acid diarrhea (BAD). In some embodiments, the IBS-D is due to bile acid malabsorption. In some embodiments, the gastrointestinal disease or condition is colitis. In some embodiments, the colitis is ulcerative colitis, microscopic colitis, or pseudomembranous colitis. In some embodiments, the enteritis is radiation-induced enteritis or chemotherapy-induced enteritis; the gastroenteritis is idiopathic gastroenteritis. In some embodiments, the gastrointestinal disease or condition is bile acid reflux with gastro-esophageal reflux disease (GERD) or bile acid reflux without GERD.
於一些實施例中，該腎疾病或病狀為腎纖維化、急性腎損傷、慢性腎損傷、缺血性腎病、糖尿病性腎病、小管間質性腎炎/腎病、腎小球性腎炎/腎病或其組合。In some embodiments, the kidney disease or condition is renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis/nephropathy, glomerulonephritis/nephropathy, or its combination.
於一些實施例中，該癌症為***癌、結腸直腸癌或肝細胞癌。In some embodiments, the cancer is prostate cancer, colorectal cancer, or hepatocellular carcinoma.
於一些實施例中，化合物1或其醫藥上可接受之鹽以口服溶液、口服懸浮液、粉末、丸劑、錠劑或膠囊之形式向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該哺乳動物投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次經由滴定時程表向該哺乳動物投與。於一些實施例中，該滴定時程表包括化合物1或其醫藥上可接受之鹽、水合物或溶劑化物之向上滴定或向下滴定，接著視情況可選的再次向上滴定。於一些實施例中，該滴定時程表包括以初始劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該初始劑量，以等於第一增量值之量增加該劑量或假如該患者不耐受該初始劑量，以等於第一增量值之量減少該劑量。於一些實施例中，該滴定時程表進一步包括：以增加之劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該增加之劑量，以等於第二增量值之量進一步增加該劑量；或以減少之劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該減少之劑量，以等於第二增量值之量視情況增加該劑量。於一些實施例中，重複該滴定時程表直至獲得最佳劑量。於一些實施例中，該最佳劑量為約30 mg、40 mg、50 mg、約60 mg、約70 mg、約80 mg、約90 mg、約100 mg、約110 mg、約120 mg、約130 mg、約140 mg、約150 mg或約160 mg化合物1。In some embodiments,
於一些實施例中，該方法進一步包括向該個體投與除了化合物1或其醫藥上可接受之鹽之至少一種附加治療劑。於一些實施例中，該至少一種附加治療劑為血管收縮素2型受體促效劑、酮己糖激酶(KHK)抑制劑、粒線體解偶聯劑或質子載體、鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、二氫神經醯胺去飽和酶1 (DES-1)抑制劑、整合素aVb1抑制劑、整合素aVb6抑制劑、類NOD受體蛋白3 (NLRP3)抑制劑、親環素抑制劑、類升糖素胜肽-1 (GLP-1)促效劑、17-β-羥基類固醇脫氫酶13型(17b-HSD 13型)抑制劑、甲狀腺激素受體β (THR-β)促效劑或其組合。In some embodiments, the method further comprises administering to the individual at least one additional therapeutic agent in addition to
於一個態樣中，本文中描述一種治療或預防肝臟疾病或病狀、脂質疾病或病症、代謝炎症介導之疾病或病症或其組合之方法，其包括向有需要個體投與為反式 -N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反式 -4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)之化合物，或其醫藥上可接受之鹽或溶劑化物。In one aspect, described herein is a method of treating or preventing a liver disease or condition, a lipid disease or condition, a metabolic inflammation-mediated disease or condition, or a combination thereof, comprising administering to an individual in need thereof a trans- N- (3-(1-Cyclopropyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methyl A compound of phenyl)cyclohexyl)methyl)cyclohexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof.
於一些實施例中，該肝臟疾病或病狀為脂肪性肝炎、膽管炎、脂肪肝病、膽汁鬱積、肝硬化、纖維化肝病、肝發炎、原發性膽汁性膽管炎、膽道閉鎖、阿拉吉歐症候群、IFALD (腸衰竭相關聯之肝病)、胃腸外營養相關聯之肝病(PNALD)、肝炎、肝細胞癌、膽管癌或其組合。於一些實施例中，該脂肪性肝炎為非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)或HIV相關聯之脂肪性肝炎。於一些實施例中，該膽管炎為原發性膽汁性膽管炎(PBC)或原發性硬化性膽管炎(PSC)。於一些實施例中，該脂肪肝病為非酒精性脂肪肝病(NAFLD)或酒精相關之脂肪肝病。於一些實施例中，該膽汁鬱積為肝內膽汁鬱積或肝外膽汁鬱積。於一些實施例中，該膽汁鬱積為妊娠期肝內膽汁鬱積或進行性家族性肝內膽汁鬱積(PFIC)。於一些實施例中，該肝硬化為HIV相關聯之肝硬化。In some embodiments, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrotic liver disease, liver inflammation, primary biliary cholangitis, biliary atresia, alajic European syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof. In some embodiments, the steatohepatitis is nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or HIV-associated steatohepatitis. In some embodiments, the cholangitis is primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or alcohol-related fatty liver disease. In some embodiments, the cholestasis is intrahepatic cholestasis or extrahepatic cholestasis. In some embodiments, the cholestasis is intrahepatic cholestasis of pregnancy or progressive familial intrahepatic cholestasis (PFIC). In some embodiments, the cirrhosis is HIV-associated cirrhosis.
於一些實施例中，該肝臟疾病或病狀為非酒精性脂肪性肝炎(NASH)。於一些實施例中，該肝臟疾病或病狀為伴隨肝纖維化之NASH。於一些實施例中，該肝臟疾病或病狀為不伴隨肝纖維化之NASH。In some embodiments, the liver disease or condition is nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease or condition is NASH with liver fibrosis. In some embodiments, the liver disease or condition is NASH without liver fibrosis.
於一些實施例中，該代謝炎症介導之疾病或病症為糖尿病。於一些實施例中，該糖尿病為2型糖尿病。In some embodiments, the metabolic inflammation-mediated disease or disorder is diabetes. In some embodiments, the diabetes is
於一些實施例中，該脂質疾病或病症為血脂異常。血脂異常為血液中之脂質之異常量。於一些實施例中，該脂質係選自甘油三酯、膽固醇及脂肪磷脂。於一些實施例中，胰島素含量之延長之升高導致血脂異常。於一些實施例中，O-GlcNAc轉移酶(OGT)之增加之含量引起血脂異常。In some embodiments, the lipid disease or disorder is dyslipidemia. Dyslipidemia is an abnormal amount of lipids in the blood. In some embodiments, the lipid is selected from triglycerides, cholesterol, and fatty phospholipids. In some embodiments, the prolonged elevation of insulin levels results in dyslipidemia. In some embodiments, increased levels of O-GlcNAc transferase (OGT) cause dyslipidemia.
於一些實施例中，該纖維化肝病為產生自以下之纖維化肝病：非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、非酒精性脂肪肝病(NAFLD)、原發性膽汁性膽管炎(PBC)、原發性硬化性膽管炎(PSC)、C型肝炎病毒(HCV)、肝硬化、威爾森氏病、HIV相關聯之脂肪性肝炎、HIV相關聯之肝硬化或先天性肝纖維化。In some embodiments, the fibrotic liver disease is a fibrotic liver disease resulting from nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), primary Biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatitis C virus (HCV), cirrhosis, Wilson's disease, HIV-associated steatohepatitis, HIV-associated cirrhosis or congenital liver fibrosis.
於一些實施例中，該肝發炎為急性肝炎、慢性肝炎、猛爆性肝炎、病毒性肝炎、細菌性肝炎、寄生蟲性肝炎、毒物及藥物誘導之肝炎、酒精性肝炎、自體免疫性肝炎、非酒精性脂肪性肝炎(NASH)、新生兒肝炎或缺血性肝炎。In some embodiments, the liver inflammation is acute hepatitis, chronic hepatitis, fulminant hepatitis, viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis , nonalcoholic steatohepatitis (NASH), neonatal hepatitis or ischemic hepatitis.
於一些實施例中，該肝炎為自體免疫性肝炎。In some embodiments, the hepatitis is autoimmune hepatitis.
於一些實施例中，該肝臟疾病或病狀為阿拉吉歐症候群。於一些實施例中，該肝臟疾病或病狀為膽道閉鎖。於一些實施例中，該肝臟疾病或病狀為肝細胞癌。於一些實施例中，該肝臟疾病或病狀為膽管癌。In some embodiments, the liver disease or condition is Alaggio syndrome. In some embodiments, the liver disease or condition is biliary atresia. In some embodiments, the liver disease or condition is hepatocellular carcinoma. In some embodiments, the liver disease or condition is cholangiocarcinoma.
於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物系統性途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物經口途徑、注射或靜脈內途逕向該個體投與。In some embodiments,
於一些實施例中，向該個體投與除了化合物1或其醫藥上可接受之鹽或溶劑化物以外之至少一種附加治療劑。In some embodiments, at least one additional therapeutic agent other than
於另一態樣中，本文中描述一種治療或預防胃腸疾病或病狀之方法，其包括向有需要個體投與為反式 -N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反式 -4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)之化合物，或其醫藥上可接受之鹽或溶劑化物。In another aspect, described herein is a method of treating or preventing a gastrointestinal disease or condition comprising administering to an individual in need thereof a trans- N- (3-(1-cyclopropyl- 1H -pyridine) azol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide ( A compound of compound 1), or a pharmaceutically acceptable salt or solvate thereof.
於一些實施例中，該胃腸疾病或病狀為壞死性小腸結腸炎、發炎性腸病(IBD)、大腸激躁症候群(IBS)、胃腸炎、輻射誘導之腸炎、假膜性結腸炎、腸炎、乳糜瀉、腸手術後發炎、移植物抗宿主疾病、膽汁酸逆流或結腸直腸癌。In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, enteritis , celiac disease, inflammation after bowel surgery, graft-versus-host disease, bile acid reflux, or colorectal cancer.
於一些實施例中，該胃腸疾病或病狀為發炎性腸病(IBD)。In some embodiments, the gastrointestinal disease or condition is inflammatory bowel disease (IBD).
於一些實施例中，該發炎性腸病(IBD)為克羅恩氏病或潰瘍性結腸炎。In some embodiments, the inflammatory bowel disease (IBD) is Crohn's disease or ulcerative colitis.
於一些實施例中，該大腸激躁症候群(IBS)為大腸激躁症候群伴腹瀉(IBS-D)、大腸激躁症候群伴便秘(IBS-C)、混合型IBS (IBS-M)、未分亞型之IBS (IBS-U)或膽汁酸腹瀉(BAD)。In some embodiments, the irritable bowel syndrome (IBS) is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unspecified Subtypes of IBS (IBS-U) or bile acid diarrhea (BAD).
於一些實施例中，該IBS-D係由於膽汁酸吸收不良。In some embodiments, the IBS-D is due to bile acid malabsorption.
於一些實施例中，該胃腸疾病或病狀為結腸炎。於一些實施例中，該結腸炎為潰瘍性結腸炎、顯微鏡性結腸炎或假膜性結腸炎。In some embodiments, the gastrointestinal disease or condition is colitis. In some embodiments, the colitis is ulcerative colitis, microscopic colitis, or pseudomembranous colitis.
於一些實施例中，該腸炎為輻射誘導之腸炎或化療誘導之腸炎。In some embodiments, the enteritis is radiation-induced enteritis or chemotherapy-induced enteritis.
於一些實施例中，該胃腸炎為特發性胃腸炎。In some embodiments, the gastroenteritis is idiopathic gastroenteritis.
於一些實施例中，該胃腸疾病或病狀為伴隨胃-食道逆流疾病(GERD)之膽汁酸逆流。於一些實施例中，該胃腸疾病或病狀為不伴隨GERD之膽汁酸逆流。In some embodiments, the gastrointestinal disease or condition is bile acid reflux associated with gastro-esophageal reflux disease (GERD). In some embodiments, the gastrointestinal disease or condition is bile acid reflux without GERD.
於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物系統性途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物非系統性途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物經口途徑、注射或靜脈內途逕向該個體投與。In some embodiments,
於另一態樣中，本文中描述一種治療或預防腎疾病或病狀之方法，其包括向有需要個體投與化合物，該化合物為反式 -N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反式 -4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物。In another aspect, described herein is a method of treating or preventing a kidney disease or condition comprising administering to an individual in need thereof a compound that is trans- N- (3-(1-cyclopropyl- 1 H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane Formamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof.
於一些實施例中，該腎疾病或病狀為腎纖維化、急性腎損傷、慢性腎損傷、缺血性腎病、糖尿病性腎病、小管間質性腎炎/腎病、腎小球性腎炎/腎病或其組合。In some embodiments, the kidney disease or condition is renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis/nephropathy, glomerulonephritis/nephropathy, or its combination.
於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物系統性途逕向該個體投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物經口途徑、注射或靜脈內途逕向該個體投與。In some embodiments,
於另一態樣中，本文中描述一種治療或預防癌症之方法，其包括向有需要個體投與化合物，該化合物為反式 -N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反式 -4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物。In another aspect, described herein is a method of treating or preventing cancer comprising administering to an individual in need thereof a compound that is trans- N- (3-(1-cyclopropyl- 1H -pyridine) azol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide ( Compound 1), or a pharmaceutically acceptable salt or solvate thereof.
於一些實施例中，該癌症為***癌、結腸直腸癌或肝細胞癌。In some embodiments, the cancer is prostate cancer, colorectal cancer, or hepatocellular carcinoma.
於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物系統性途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽或溶劑化物經口途徑、注射或靜脈內途逕向該個體投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽以約1 mg至約300 mg化合物1之劑量向該哺乳動物投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽系統性途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽經口途徑、注射或靜脈內途逕向該個體投與。於一些實施例中，化合物1或其醫藥上可接受之鹽以口服溶液、口服懸浮液、粉末、丸劑、錠劑或膠囊之形式向該哺乳動物投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該哺乳動物投與。In some embodiments,
於一些實施例中，本文中所揭示之治療方法中之任一者進一步包括向該個體投與除了化合物1或其醫藥上可接受之鹽之至少一種附加治療劑。於一些實施例中，該至少一種附加治療劑為血管收縮素2型受體促效劑、酮己糖激酶(KHK)抑制劑、粒線體解偶聯劑或質子載體、鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、二氫神經醯胺去飽和酶1 (DES-1)抑制劑、整合素aVb1抑制劑、整合素aVb6抑制劑、類NOD受體蛋白3 (NLRP3)抑制劑、親環素抑制劑、類升糖素胜肽-1 (GLP-1)促效劑、17-β-羥基類固醇脫氫酶13型(17b-HSD 13型)抑制劑、甲狀腺激素受體β (THR-β)促效劑或其組合。In some embodiments, any of the methods of treatment disclosed herein further comprises administering to the individual at least one additional therapeutic agent in addition to
於一個態樣中，本文中描述一種治療或預防個體之脂肪肝病之方法，其包括向該患有脂肪肝病之個體投與化合物，該化合物為反式 -N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反式 -4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物。於一些實施例中，該脂肪肝病為非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)或酒精性脂肪性肝炎(ASH)。In one aspect, described herein is a method of treating or preventing fatty liver disease in an individual comprising administering to the individual having fatty liver disease a compound that is trans- N- (3-(1-cyclopropane) yl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cycle Hexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).
於一些實施例中，治療脂肪肝病包括肝脂肪減少、肝組織學改善、肝血液測試改善、膽汁鬱積性搔癢改善或其組合。In some embodiments, treating fatty liver disease comprises reduction in liver fat, improvement in liver histology, improvement in liver blood tests, improvement in cholestatic pruritus, or a combination thereof.
於一些實施例中，該患有脂肪肝病之個體患有糖尿病。於一些實施例中，該糖尿病為2型糖尿病。In some embodiments, the individual with fatty liver disease has diabetes. In some embodiments, the diabetes is
於一些實施例中，化合物1或其醫藥上可接受之鹽以約10 mg至約100 mg化合物1之劑量向該哺乳動物經口投與。於一些實施例中，化合物1或其醫藥上可接受之鹽以口服溶液、口服懸浮液、粉末、丸劑、錠劑或膠囊之形式向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該哺乳動物投與。In some embodiments,
於一些實施例中，化合物1或其醫藥上可接受之鹽按照滴定時程表向該哺乳動物經口投與。於一些實施例中，該滴定時程表包括每日投與約50 mg化合物1或其醫藥上可接受之鹽持續一段時間，接著每日投與約80 mg化合物1或其醫藥上可接受之鹽。於一些實施例中，該時間段包括1天、約1週、約2週、約3週、約4週、約5週、約6週、約7週、約8週、約9週、約10週、約11週或約12週。In some embodiments,
於一些實施例中，本文中所揭示之治療方法中之任一者進一步包括向該個體投與除了化合物1或其醫藥上可接受之鹽以外之至少一種附加治療劑。於一些實施例中，該至少一種附加治療劑為鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、類升糖素胜肽-1 (GLP-1)促效劑或其組合。In some embodiments, any of the methods of treatment disclosed herein further comprises administering to the individual at least one additional therapeutic agent other than
於另一態樣中，本文中描述一種治療或預防個體之脂肪肝病之方法，其包括向該患有脂肪肝病之個體投與化合物，該化合物為反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(化合物1)，或其醫藥上可接受之鹽或溶劑化物。於一些實施例中，該脂肪肝病為非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)或酒精性脂肪性肝炎(ASH)。於一些實施例中，治療脂肪肝病包括肝脂肪減少、肝組織學改善、肝血液測試改善、膽汁鬱積性搔癢改善或其組合。於一些實施例中，該個體患有糖尿病。於一些實施例中，該糖尿病為2型糖尿病。於一些實施例中，化合物1或其醫藥上可接受之鹽以約10 mg至約100 mg化合物1之劑量向該哺乳動物經口投與。於一些實施例中，化合物1或其醫藥上可接受之鹽以口服溶液、口服懸浮液、粉末、丸劑、錠劑或膠囊之形式向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日向該哺乳動物投與。於一些實施例中，化合物1或其醫藥上可接受之鹽係每日一次向該哺乳動物投與。In another aspect, described herein is a method of treating or preventing fatty liver disease in an individual comprising administering to the individual suffering from fatty liver disease a compound that is trans- N- (3-(1-cyclic Propyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) Cyclohexanecarboxamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH). In some embodiments, treating fatty liver disease comprises reduction in liver fat, improvement in liver histology, improvement in liver blood tests, improvement in cholestatic pruritus, or a combination thereof. In some embodiments, the individual has diabetes. In some embodiments, the diabetes is
於一些實施例中，化合物1或其醫藥上可接受之鹽按照滴定時程表向該哺乳動物經口投與。於一些實施例中，該滴定時程表包括每日投與約50 mg化合物1或其醫藥上可接受之鹽持續一段時間，接著每日投與約80 mg化合物1或其醫藥上可接受之鹽。於一些實施例中，該時間段包括1天、約1週、約2週、約3週、約4週、約5週、約6週、約7週、約8週、約9週、約10週、約11週或約12週。In some embodiments,
於一些實施例中，該方法進一步包括向該個體投與除了化合物1或其醫藥上可接受之鹽以外之至少一種附加治療劑。於一些實施例中，該至少一種附加治療劑為血管收縮素2型受體促效劑、酮己糖激酶(KHK)抑制劑、粒線體解偶聯劑或質子載體、鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、二氫神經醯胺去飽和酶1 (DES-1)抑制劑、整合素aVb1抑制劑、整合素aVb6抑制劑、類NOD受體蛋白3 (NLRP3)抑制劑、親環素抑制劑、類升糖素胜肽-1 (GLP-1)促效劑、17-β-羥基類固醇脫氫酶13型(17b-HSD 13型)抑制劑、甲狀腺激素受體β (THR-β)促效劑或其組合。於一些實施例中，該至少一種附加治療劑為鈉-葡萄糖轉運蛋白2 (SGLT2)抑制劑、鈉-葡萄糖轉運蛋白1/2 (SGLT1/2)共抑制劑、類升糖素胜肽-1 (GLP-1)促效劑或其組合。In some embodiments, the method further comprises administering to the individual at least one additional therapeutic agent in addition to
提供製品，該等製品包含包裝材料、該包裝材料內之本文中所述化合物或其醫藥上可接受之鹽及指示FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於調節FXR活性或用於治療、預防或改善將自調節FXR活性受益之疾病或病狀之一或多種症狀的標籤。Articles of manufacture are provided comprising packaging material, within the packaging material a compound described herein, or a pharmaceutically acceptable salt thereof, and indicating that an FXR agonist (eg,
本文中所述之化合物、方法及組合物之其他目標、特徵及優點將自下列實施方式變得顯然。然而，應瞭解，雖然指示特定實施例，但是實施方式及特定實例僅經由說明提供，因為本發明之精神及範圍內之各種變化及修改將自此實施方式對熟習此項技術者變得顯然。Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following examples. It should be understood, however, that while specific embodiments are indicated, implementations and specific examples are provided by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this embodiment.
交互參照cross reference
本申請案主張2020年3月18日申請之美國臨時專利申請案第62/991,301號及2020年6月1日申請之美國臨時專利申請案第63/032,851號之權益；該等案各者之全文係以引用的方式併入本文中。This application claims the benefit of US Provisional Patent Application No. 62/991,301, filed March 18, 2020, and US Provisional Patent Application No. 63/032,851, filed June 1, 2020; The entire contents are incorporated herein by reference.
FXR於抑制肝發炎及調節脂質代謝中起著關鍵作用。細胞核激素受體法尼醇X受體(亦稱作FXR或細胞核受體亞家族1，H組，成員4 (NR1H4)) (OMIM: 603826)作為膽汁酸代謝之調節劑起作用。FXR為於各種組織(包括腎上腺、腎、胃、十二指腸、空腸、回腸、結腸、膽囊、肝、巨噬細胞及白色及棕色脂肪組織)中表現之經配位體活化之轉錄受體。膽汁酸作為FXR之內源性配位體起作用使得膽汁酸之腸及全身釋放誘導基因表現網路中之FXR指導之變化。膽汁酸為膽固醇之主要氧化產物，及於一些情況下，在分泌至腸中後，為膽固醇吸收之調節劑。膽固醇轉化成膽汁酸之速率限制步驟由細胞色素p450酶膽固醇7-α-羥化酶(CYP7A1)催化及於肝中發生。FXR之活化藉由增加肝小異二聚體搭檔(SHP) (亦稱作細胞核受體亞家族0，B組，成員2；或NR0B2)之表現程度及小鼠中之纖維母細胞生長因子15 (FGF15)及人類中之纖維母細胞生長因子19 (FGF-19)之腸表現來抑制CYP7A1之轉錄。SHP通過其與肝受體同源物(LRH-1) (針對CYP7A1基因表現必需之細胞核受體)相互作用以形成非功能性異二聚體抑制LRH-1。於一些情況下，FGF15/19自腸釋放，然後活化肝中之纖維母細胞生長因子受體4，從而導致絲裂原活化之蛋白質激酶(MAPK)信號路徑之活化，其會抑制Cyp7A1。FXR plays a key role in inhibiting liver inflammation and regulating lipid metabolism. The nuclear hormone receptor farnesoid X receptor (also known as FXR or
於一些實施例中，FXR之活化導致肝發炎之減少。例如，已顯示FXR之活化拮抗涉及肝發炎之NF-κB路徑(Wang等人，Hepatology 48(5): 1632-1643, 2008)。於一些實施例中，FXR之活化減少胃腸道發炎。例如，FXR之活化減少發炎性細胞激素(諸如介白素(IL) 1-β、IL-2及IL-6)、腫瘤壞死因子-α(TNF-α)及干擾素-γ之產生(Stojancevic等人，Can J Gastroenterol , 26(9): 631-637, 2012)。In some embodiments, activation of FXR results in a reduction in liver inflammation. For example, activation of FXR has been shown to antagonize the NF-κB pathway involved in liver inflammation (Wang et al., Hepatology 48(5): 1632-1643, 2008). In some embodiments, activation of FXR reduces gastrointestinal inflammation. For example, activation of FXR reduces the production of inflammatory cytokines such as interleukin (IL) 1-beta, IL-2, and IL-6, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (Stojancevic et al, Can J Gastroenterol , 26(9): 631-637, 2012).
對特定聚焦於涉及肝病(諸如纖維化、代謝性及發炎性肝病)之分子靶及/或路徑之療法存在未滿足的需求。There is an unmet need for therapies that specifically focus on molecular targets and/or pathways involved in liver diseases such as fibrosis, metabolic and inflammatory liver diseases.
於某些實施例中，本文中揭示治療有需要個體之肝病之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑，例如，化合物1或其醫藥上可接受之鹽。In certain embodiments, disclosed herein are methods of treating liver disease in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist, eg,
於某些實施例中，本文中進一步揭示治療有需要個體之代謝性肝病之方法，其包括向該個體投與FXR促效劑，例如，化合物1或其醫藥上可接受之鹽。In certain embodiments, further disclosed herein are methods of treating metabolic liver disease in an individual in need thereof, comprising administering to the individual an FXR agonist, eg,
於某些實施例中，本文中進一步揭示治療有需要個體之纖維化肝病之方法，其包括向該個體投與FXR促效劑，例如，化合物1或其醫藥上可接受之鹽。In certain embodiments, further disclosed herein are methods of treating fibrotic liver disease in an individual in need thereof, comprising administering to the individual an FXR agonist, eg,
於某些實施例中，本文中進一步揭示治療有需要個體之胃腸疾病之方法，其包括向該個體投與FXR促效劑，例如，化合物1或其醫藥上可接受之鹽。In certain embodiments, further disclosed herein are methods of treating a gastrointestinal disorder in an individual in need thereof, comprising administering to the individual an FXR agonist, eg,
於某些實施例中，本文中進一步揭示治療有需要個體之發炎之方法，其包括向該個體投與FXR促效劑，例如，化合物1或其醫藥上可接受之鹽。In certain embodiments, further disclosed herein are methods of treating inflammation in an individual in need thereof, comprising administering to the individual an FXR agonist, eg,
此外，於某些實施例中，本文中揭示醫藥組合物，其包含FXR促效劑，例如，化合物1或其醫藥上可接受之鹽。肝病 Furthermore, in certain embodiments, disclosed herein are pharmaceutical compositions comprising an FXR agonist, eg,
於某些實施例中，本文中揭示治療或預防有需要個體之肝病之方法，其包括向該個體投與FXR促效劑。於一些實施例中，向該個體投與除了FXR促效劑之至少一種附加治療劑。於一些實施例中，該FXR促效劑為化合物1或其醫藥上可接受之鹽。In certain embodiments, disclosed herein are methods of treating or preventing liver disease in an individual in need thereof, comprising administering to the individual an FXR agonist. In some embodiments, at least one additional therapeutic agent in addition to the FXR agonist is administered to the individual. In some embodiments, the FXR agonist is
於一些實施例中，該肝病為酒精性肝病或非酒精性肝病。於一些實施例中，該肝病為酒精性肝病。示例性酒精性肝臟疾病或病狀包括(但不限於)脂肪肝(脂肪變性)、肝硬化、酒精性脂肪性肝炎(ASH)或酒精性肝炎。於一些實施例中，向有需要個體投與FXR促效劑作為治療或預防脂肪肝(脂肪變性)、肝硬化、酒精性脂肪性肝炎(ASH)或酒精性肝炎之方法。脂肪變性 In some embodiments, the liver disease is alcoholic liver disease or non-alcoholic liver disease. In some embodiments, the liver disease is alcoholic liver disease. Exemplary alcoholic liver diseases or conditions include, but are not limited to, fatty liver (steatosis), cirrhosis, alcoholic steatohepatitis (ASH), or alcoholic hepatitis. In some embodiments, an FXR agonist is administered to an individual in need thereof as a method of treating or preventing fatty liver (steatosis), cirrhosis, alcoholic steatohepatitis (ASH) or alcoholic hepatitis. steatosis
脂肪變性(亦稱作脂肪變化、脂肪(adipose)變性或脂肪(fatty)變性)為描述脂質於細胞內異常滯留之過程。Steatosis (also known as adipose change, adipose degeneration, or fatty degeneration) is a process that describes the abnormal retention of lipids within cells.
脂肪變性最常影響肝(脂質代謝之主要器官)，其中該病狀通常稱作脂肪肝病。脂肪變性亦可於其他器官(包括腎、心臟及肌肉)中發生。與脂肪變性相關聯之風險因素係各種各樣，及包括(但不限於)糖尿病、蛋白質營養不良、高血壓、細胞毒素、肥胖症、缺氧及睡眠呼吸中止症。Steatosis most commonly affects the liver, the major organ of lipid metabolism, where the condition is often referred to as fatty liver disease. Steatosis can also occur in other organs, including kidney, heart, and muscle. Risk factors associated with steatosis are various and include, but are not limited to, diabetes, protein malnutrition, hypertension, cytotoxicity, obesity, hypoxia, and sleep apnea.
脂肪變性反映正常合成及消除甘油三酯脂肪之過程受損。過量脂質於取代細胞質之囊泡中累積。雖然於輕度病例中對細胞不會特別有害，但是大量累積可破壞細胞構成，及於嚴重病例中細胞可甚至破裂。Steatosis reflects impairment of the normal synthesis and elimination of triglyceride fats. Excess lipids accumulate in vesicles that replace the cytoplasm. Although not particularly harmful to cells in mild cases, large accumulations can disrupt cellularity, and in severe cases cells can even rupture.
於一些實施例中，FXR促效劑向患有脂肪變性之哺乳動物之投與減少該哺乳動物之脂肪變性。In some embodiments, administration of an FXR agonist to a mammal with steatosis reduces steatosis in the mammal.
於一些實例中，脂肪變性減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，脂肪變性之程度係相對於不利用FXR促效劑治療之哺乳動物之脂肪變性之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some examples, steatosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of steatosis is relative to the degree of steatosis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一些實例中，FXR促效劑向患有脂肪變性之哺乳動物之投與減少哺乳動物之肝脂肪至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。In some examples, administration of an FXR agonist to a mammal with steatosis reduces liver fat in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more.
肝脂肪變性(亦稱作脂肪肝)為其中過量甘油三酯脂質於肝細胞中累積之病狀及亦可伴隨肝之進行性發炎(其亦稱作脂肪性肝炎)。於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之脂肪肝(肝脂肪變性)或脂肪性肝炎。於一些實例中，該FXR促效劑減少哺乳動物之肝脂肪變性或脂肪性肝炎至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，肝脂肪變性或脂肪性肝炎減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝脂肪變性或脂肪性肝炎之程度係相對於不利用FXR促效劑治療之哺乳動物之肝脂肪變性或脂肪性肝炎之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。肝硬化 Hepatic steatosis (also known as fatty liver) is a condition in which excess triglyceride lipids accumulate in hepatocytes and can also be accompanied by progressive inflammation of the liver (also known as steatohepatitis). In some embodiments, the FXR agonists disclosed herein reduce fatty liver (hepatic steatosis) or steatohepatitis in mammals. In some examples, the FXR agonist reduces hepatic steatosis or steatohepatitis in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more many. In some examples, hepatic steatosis or steatohepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of hepatic steatosis or steatohepatitis is relative to the degree of hepatic steatosis or steatohepatitis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. cirrhosis
肝硬化為其中肝經歷影響其功能之長期損傷之病狀。肝硬化之症狀包括(但不限於)疲勞、小腿腫脹、黃疸、容易擦傷、腹部積液或蜘蛛狀血管。肝硬化最常由酒精、B型肝炎、C型肝炎及非酒精性肝病引起。於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之肝硬化。於一些實例中，FXR促效劑減少哺乳動物之肝硬化至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，肝硬化之程度減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝硬化之程度係相對於不利用FXR促效劑治療之哺乳動物之肝硬化之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。酒精性脂肪性肝炎 (ASH) Cirrhosis is a condition in which the liver undergoes long-term damage that affects its function. Symptoms of cirrhosis include, but are not limited to, fatigue, swollen lower legs, jaundice, easy bruising, fluid in the abdomen, or spider veins. Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C, and nonalcoholic liver disease. In some embodiments, the FXR agonists disclosed herein reduce liver cirrhosis in mammals. In some examples, the FXR agonist reduces cirrhosis in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some examples, the degree of cirrhosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of cirrhosis is relative to the degree of cirrhosis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Alcoholic Steatohepatitis (ASH)
酒精性脂肪性肝炎為其中由於長期攝入酒精所致過量甘油三酯脂質於肝細胞中累積之病狀及可伴隨肝之進行性發炎。於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之酒精性脂肪性肝炎。於一些實例中，FXR促效劑減少哺乳動物之酒精性脂肪性肝炎至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，酒精性脂肪性肝炎之程度減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，酒精性脂肪性肝炎之程度係相對於不利用FXR促效劑治療之哺乳動物之酒精性脂肪性肝炎之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。酒精性肝炎 Alcoholic steatohepatitis is a condition in which excess triglyceride lipids accumulate in liver cells due to chronic alcohol intake and may be accompanied by progressive inflammation of the liver. In some embodiments, the FXR agonists disclosed herein reduce alcoholic steatohepatitis in mammals. In some examples, the FXR agonist reduces alcoholic steatohepatitis in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some examples, the degree of alcoholic steatohepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of alcoholic steatohepatitis is relative to the extent of alcoholic steatohepatitis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. alcoholic hepatitis
酒精性肝炎為由於過量攝入酒精所致之肝發炎。其通常與脂肪肝相關聯及促進纖維化之進展，其導致肝硬化。於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之酒精性肝炎。於一些實例中，FXR促效劑減少哺乳動物之酒精性肝炎至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，酒精性肝炎之程度減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，酒精性肝炎之程度係相對於不利用FXR促效劑治療之哺乳動物之酒精性肝炎之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 代謝性肝病 Alcoholic hepatitis is inflammation of the liver caused by excessive intake of alcohol. It is often associated with fatty liver and promotes the progression of fibrosis, which leads to cirrhosis. In some embodiments, the FXR agonists disclosed herein reduce alcoholic hepatitis in a mammal. In some examples, the FXR agonist reduces alcoholic hepatitis in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some examples, the degree of alcoholic hepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of alcoholic hepatitis is relative to the extent of alcoholic hepatitis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. metabolic liver disease
於一些實施例中，向有需要個體投與法尼醇X受體(FXR)促效劑作為治療或預防非酒精性肝病之方法。於一些實施例中，該非酒精性肝病為代謝性肝病。於一些實施例中，該代謝性疾病伴隨肝纖維化。於一些實施例中，該代謝性肝病係由肥胖症、高血壓、血脂異常、2型糖尿病、葡萄糖耐受受損、空腹血糖受損、或胰島素抗性引起。 In some embodiments, a farnesoid X receptor (FXR) agonist is administered to an individual in need thereof as a method of treating or preventing nonalcoholic liver disease. In some embodiments, the nonalcoholic liver disease is metabolic liver disease. In some embodiments, the metabolic disease is accompanied by liver fibrosis. In some embodiments, the metabolic liver disease is caused by obesity, hypertension, dyslipidemia,
於某些實施例中，本文中揭示治療或預防有需要個體之代謝性肝病之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑。於一些實施例中，該代謝性肝病為非酒精性脂肪肝病(NAFLD)、肝內膽汁鬱積或肝外膽汁鬱積。於一些實施例中，向有需要個體投與法尼醇X受體(FXR)促效劑作為治療或預防非酒精性脂肪肝病(NAFLD)、肝內膽汁鬱積或肝外膽汁鬱積之方法。 In certain embodiments, disclosed herein are methods of treating or preventing metabolic liver disease in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist. In some embodiments, the metabolic liver disease is nonalcoholic fatty liver disease (NAFLD), intrahepatic cholestasis, or extrahepatic cholestasis. In some embodiments, a farnesoid X receptor (FXR) agonist is administered to an individual in need thereof as a method of treating or preventing nonalcoholic fatty liver disease (NAFLD), intrahepatic cholestasis, or extrahepatic cholestasis.
於一些實施例中，代謝過程，諸如膽汁酸合成、膽汁酸循環、葡萄糖代謝、脂質代謝或胰島素敏感性之調節係藉由活化FXR調節。此外，於一些實施例中，代謝過程，諸如膽汁酸合成、膽汁酸循環、葡萄糖代謝、脂質代謝或胰島素敏感性之失調導致代謝性疾病，諸如糖尿病或糖尿病相關病狀或病症、酒精性或非酒精性肝臟疾病或病狀、腸發炎或細胞增殖性病症。In some embodiments, the modulation of metabolic processes, such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism, or insulin sensitivity, is modulated by activating FXR. Furthermore, in some embodiments, dysregulation of metabolic processes such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism or insulin sensitivity results in metabolic diseases such as diabetes or diabetes-related conditions or disorders, alcoholic or non-alcoholic Alcoholic liver disease or condition, intestinal inflammation or cell proliferative disorder.
於一些實施例中，升高之膽汁酸含量與胰島素抗性相關聯。例如，胰島素抗性有時導致減少攝入來自血液之葡萄糖及增加肝中葡萄糖重新產生。於一些實例中，已顯示膽汁酸之腸隔離藉由促進類升糖素胜肽-1 (GLP-1)自腸L-細胞之分泌來改善胰島素抗性。GLP-1為源自胰高血糖素原基因之轉錄產物之腸促胰島素。其對攝入食物反應而釋放及控制食欲及胃腸功能及促進胰島素自胰腺分泌。GLP-1之生物活性形式包括GLP-1-(7-37)及GLP-1-(7-36)NH2 ，其自胰高血糖素原分子之選擇性裂解產生。In some embodiments, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance sometimes results in reduced intake of glucose from the blood and increased re-production of glucose in the liver. In some examples, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting secretion of Glucoid-Like Peptide-1 (GLP-1 ) from intestinal L-cells. GLP-1 is an incretin derived from the transcript of the proglucagon gene. It is released in response to food intake and controls appetite and gastrointestinal function and promotes insulin secretion from the pancreas. GLP-1 comprising the biologically active forms of GLP-1- (7-37) and GLP-1- (7-36) NH 2 , which is selectively cleaved from the glucagon molecule to produce the original.
於一些實施例中，FXR之活化亦與胰多肽折疊，諸如肽YY (PYY或PYY3-36)之分泌相關。於一些實例中，肽YY為調節下丘腦及腦幹(參與獎勵處理之腦之區域)內之神經活性之腸激素肽。於一些實例中，減少之PYY之含量與增加之食欲及增重相關。In some embodiments, activation of FXR is also associated with pancreatic polypeptide folding, such as secretion of peptide YY (PYY or PYY3-36). In some examples, peptide YY is an enterohormonal peptide that modulates neural activity within the hypothalamus and brainstem (regions of the brain involved in reward processing). In some instances, decreased levels of PYY correlate with increased appetite and weight gain.
於一些實例中，FXR之活化間接導致血漿甘油三酯之減少。甘油三酯自血液之清除係由於脂蛋白脂肪酶(LPL)。LPL活性藉由在FXR活化後於肝中誘導其活化子載脂蛋白CII及抑制其抑制劑載脂蛋白CIII出現而增強。In some instances, activation of FXR indirectly results in a reduction in plasma triglycerides. The clearance of triglycerides from the blood is due to lipoprotein lipase (LPL). LPL activity is enhanced by induction of its activator apolipoprotein CII and inhibition of its inhibitor apolipoprotein CIII in the liver following activation of FXR.
於一些情況下，FXR之活化進一步調節能量消耗，諸如脂肪細胞分化及功能。脂肪組織包括脂肪細胞(adipocyte / fat cell)。於一些實例中，脂肪細胞進一步分化成棕色脂肪組織(BAT)或白色脂肪組織(WAT)。BAT之功能為產生體熱，而WAT功能為脂肪儲存組織。於一些實施例中，FXR之活化增強WAT之生熱及變棕色。於一些實施例中，FXR之活化增加BAT質量。In some cases, activation of FXR further regulates energy expenditure, such as adipocyte differentiation and function. Adipose tissue includes adipocytes (adipocytes/fat cells). In some examples, adipocytes are further differentiated into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to generate body heat, while the function of WAT is to store fat. In some embodiments, activation of FXR enhances thermogenesis and browning of WAT. In some embodiments, activation of FXR increases BAT mass.
於一些實例中，FXR於腸中廣泛表現。於一些情況下，已顯示FXR之活化誘導FGF-19 (或小鼠中FGF15)於腸中之表現及分泌。FGF-19為調節膽汁酸合成以及在葡萄糖代謝、脂質代謝及能量消耗方面發揮作用之激素。於一些實例中，亦已觀察到FGF-19調節脂肪細胞功能及分化。的確，研究已顯示FGF-19向高脂肪飲食小鼠之投與增加能量消耗，調節脂肪細胞分化及功能，逆轉增重，及改善胰島素抗性(參見，Fu等人，「Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.」Endocrinology 145:2594-2603 (2004))。In some instances, FXR is widely expressed in the intestine. In some cases, activation of FXR has been shown to induce the expression and secretion of FGF-19 (or FGF15 in mice) in the gut. FGF-19 is a hormone that regulates bile acid synthesis and plays a role in glucose metabolism, lipid metabolism and energy expenditure. In some instances, FGF-19 has also been observed to regulate adipocyte function and differentiation. Indeed, studies have shown that administration of FGF-19 to mice on a high-fat diet increases energy expenditure, modulates adipocyte differentiation and function, reverses weight gain, and improves insulin resistance (see, Fu et al., "Fibroblast growth factor 19 increases Metabolic rate and reverses dietary and leptin-deficient diabetes." Endocrinology 145:2594-2603 (2004)).
於一些情況下，亦已顯示腸FXR活性涉及減少微生物組之過度生長，諸如在進食期間(Li等人，Nat Commun 4:2384, 2013)。例如，研究顯示FXR之活化與回腸中之若干基因(諸如Ang2 、iNos 及Il18 )之增加之表現相關，該等基因已確立抗菌作用(Inagaki等人，Proc Natl Acad Sci U S A 103:3920-3925, 2006)。In some cases, intestinal FXR activity has also been shown to be involved in reducing microbiome overgrowth, such as during feeding (Li et al., Nat Commun 4:2384, 2013). For example, studies have shown that the increase in activation of several genes in the ileum (such as Ang2, iNos and IL18) of FXR expression of related genes such antibacterial effect has been established (by Inagaki et al., Proc Natl Acad Sci USA 103: 3920-3925, 2006).
G蛋白偶合膽汁酸受體1 (亦稱作GPBAR2、GPCR19、膽汁酸之膜型受體或M-BAR或TGR5)為膽汁酸之細胞表面受體。在利用膽汁酸活化後，TGR5誘導細胞內cAMP之產生，由於BAT中之脫碘酶(DIO2)之活化，其然後觸發三碘甲狀腺原胺酸之增加，從而導致增加之能量消耗。 非酒精性脂肪肝病 (NAFLD) G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, membrane-type receptor for bile acids or M-BAR or TGR5) is a cell surface receptor for bile acids. Upon activation with bile acids, TGR5 induces the production of intracellular cAMP, which then triggers an increase in triiodothyronine due to activation of deiodinase (DIO2) in BAT, resulting in increased energy expenditure. Nonalcoholic Fatty Liver Disease (NAFLD)
非酒精性脂肪肝病(NAFLD)係與由於非過量酒精攝入之原因之肝中之過量脂肪(脂肪變性)相關聯。NAFLD可顯示為單純脂肪變性或伴隨發炎及肝損傷之脂肪變性，將其歸類為非酒精性脂肪性肝炎(NASH)。於一些實施例中，NAFLD係與肥胖症、2型糖尿病及代謝症候群相關聯。代謝症候群為至少三種醫療狀況之聚集，該等狀況包括(但不限於)肥胖症、升高之血壓、升高之空腹血漿葡萄糖、高血清甘油三酯或高低密度脂蛋白(LDL)含量。Nonalcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (steatosis) due to causes other than excessive alcohol intake. NAFLD can manifest as simple steatosis or steatosis with inflammation and liver damage, classifying it as nonalcoholic steatohepatitis (NASH). In some embodiments, NAFLD is associated with obesity,
根據國立衛生研究院(National Institutes of Health)，美國約30至40%之成人患有NAFLD及彼等中之約20%患有NASH，其特徵在於肝發炎及球囊擴張。隨著時間，患有NASH之個體可發展肝之瘢痕或纖維化，其可進展為肝硬化。診斷患有NASH之患者之約40%進展為更晚期纖維化或肝硬化(纖維化2期及更高)，其增加肝細胞癌或肝癌以及心血管疾病之風險。NASH通常與肥胖症及2型糖尿病相關聯。According to the National Institutes of Health, approximately 30 to 40% of adults in the United States suffer from NAFLD and approximately 20% of them suffer from NASH, which is characterized by liver inflammation and balloon dilation. Over time, individuals with NASH can develop scarring or fibrosis of the liver, which can progress to cirrhosis. Approximately 40% of patients diagnosed with NASH progress to more advanced fibrosis or cirrhosis (
於一些實施例中，本文中所揭示之FXR促效劑係用於治療NAFLD。於一些實例中，FXR促效劑減少哺乳動物之NAFLD至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，NAFLD減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，NAFLD之程度係相對於不利用FXR促效劑治療之哺乳動物之NAFLD之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。膽汁鬱積 In some embodiments, the FXR agonists disclosed herein are used to treat NAFLD. In some examples, the FXR agonist reduces NAFLD in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, NAFLD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of NAFLD is relative to the extent of NAFLD in mammals not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Cholestasis
膽汁鬱積為膽汁流動受損或停止，於一些情況下，其由於膽汁酸及其他毒素於肝中積聚而引起肝毒性。於一些實施例中，膽汁鬱積為肝內膽汁鬱積或肝外膽汁鬱積。於一些實施例中，肝內膽汁鬱積係由以下引起：澱粉樣變性、肝之細菌性膿腫、完全經靜脈內飼喂、淋巴瘤、妊娠、原發性膽汁性膽管炎、原發性或轉移性肝癌、膽管癌、原發性硬化性膽管炎、結節病、通過血液傳播之嚴重感染(膿毒病)、結核病或病毒性肝炎。於一些實施例中，肝外膽汁鬱積係由以下引起：膽管腫瘤、膽管之囊腫狹窄(狹窄)、總膽管結石、胰炎、胰腺腫瘤或假囊腫、由於附近腫塊或腫瘤對膽管之壓力、或原發性硬化性膽管炎。於一些實施例中，膽汁鬱積係由藥物引起。於一些實施例中，膽汁鬱積係由諸如胺比西林(ampicillin)及其他盤尼西林(penicillin)、合成代謝類固醇、口服避孕藥丸、氯丙嗪(chlorpromazine)、西咪替丁(cimetidine)、***、丙咪嗪(imipramine)、普魯氯嗪(prochlorperazine)、特比萘芬(terbinafine)或甲苯磺丁脲(tolbutamide)之抗生素引起。Cholestasis is impaired or stopped bile flow, which in some cases causes liver toxicity due to the accumulation of bile acids and other toxins in the liver. In some embodiments, the cholestasis is intrahepatic cholestasis or extrahepatic cholestasis. In some embodiments, intrahepatic cholestasis is caused by amyloidosis, bacterial abscess of the liver, complete intravenous feeding, lymphoma, pregnancy, primary biliary cholangitis, primary or metastatic Liver cancer, cholangiocarcinoma, primary sclerosing cholangitis, sarcoidosis, serious infections transmitted through the blood (sepsis), tuberculosis, or viral hepatitis. In some embodiments, extrahepatic cholestasis is caused by a bile duct tumor, cystic stricture (stenosis) of the bile duct, common bile duct stones, pancreatitis, pancreatic tumor or pseudocyst, pressure on the bile duct due to a nearby mass or tumor, or Primary sclerosing cholangitis. In some embodiments, the cholestasis is caused by a drug. In some embodiments, the cholestasis is caused by factors such as ampicillin and other penicillins, anabolic steroids, oral contraceptive pills, chlorpromazine, cimetidine, estradiol , imipramine (imipramine), prochlorperazine (prochlorperazine), terbinafine (terbinafine) or tolbutamide (tolbutamide) antibiotics caused.
於一些實例中，膽汁鬱積為許多肝病之分量，該等肝病包括(但不限於)膽石病、妊娠膽汁鬱積、原發性膽汁性膽管炎(PBC)及原發性硬化性膽管炎(PSC)。於一些實例中，阻塞係由於膽石、膽道損傷、藥物、一或多種另外肝病或癌症。於一些情況下，膽汁酸之腸肝循環使脂肪及脂溶性維生素能自腸吸收及允許膽固醇、毒素及代謝副產物(諸如膽紅素)自肝消除。於一些情況下，FXR之活化誘導微管膽汁轉運蛋白BSEP (ABCB11)及耐多種藥物性相關之蛋白2 (MRP2；ABCC2, cMOAT)之表現，及抑制參與膽汁酸生物合成之基因，諸如例如固醇12α-羥化酶(CYP8B1)及CYP7A1。In some instances, cholestasis is a component of many liver diseases including, but not limited to, cholelithiasis, cholestasis of pregnancy, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). ). In some instances, the obstruction is due to gallstones, bile duct damage, drugs, one or more additional liver diseases, or cancer. In some cases, enterohepatic circulation of bile acids enables absorption of fats and fat-soluble vitamins from the gut and allows cholesterol, toxins, and metabolic byproducts (such as bilirubin) to be eliminated from the liver. In some cases, activation of FXR induces expression of the microtubule bile transporter BSEP (ABCB11) and polydrug resistance-related protein 2 (MRP2; ABCC2, cMOAT), and inhibits genes involved in bile acid biosynthesis, such as, for example, solid Alcohol 12α-hydroxylase (CYP8B1) and CYP7A1.
於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之膽汁鬱積。於一些實例中，FXR促效劑減少哺乳動物之膽汁鬱積至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，膽汁鬱積減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，膽汁鬱積之程度係相對於不利用FXR促效劑治療之哺乳動物之膽汁鬱積之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 纖維化肝病 In some embodiments, the FXR agonists disclosed herein are used to treat cholestasis in mammals. In some examples, the FXR agonist reduces mammalian cholestasis by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, cholestasis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of cholestasis is relative to the degree of cholestasis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Fibrotic liver disease
於某些實施例中，本文中揭示治療或預防有需要個體之纖維化肝病之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑。於一些實施例中，該纖維化肝病包括肝纖維化。於一些實施例中，該纖維化肝病係由以下引起：α-1抗胰蛋白酶缺乏、銅貯積病、果糖血症、半乳糖血症、糖原貯積病、鐵超載症候群、脂質異常、過氧化物酶體病症、酪胺酸血症、細菌感染、寄生蟲感染、病毒感染、影響肝血流量之病症、藥物或化學品、或機械阻塞。於一些實施例中，該影響肝血流量之纖維化肝病為布加氏(Budd-Chiari)症候群、心臟衰竭、肝靜脈閉塞病、或門靜脈血栓形成。於一些實施例中，該引起纖維化肝病之藥物或化學品為胺碘酮(amiodarone)、氯丙嗪、異菸肼(isoniazid)、胺甲喋呤(methotrexate)、甲基多巴(methyldopa)、酚丁(oxyphenisatin)、醇或甲苯磺丁脲。於一些實施例中，該引起纖維化肝病之機械阻塞為由於肝手術之肝瘢痕或由於壓實之膽石之膽管狹窄。In certain embodiments, disclosed herein are methods of treating or preventing fibrotic liver disease in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist. In some embodiments, the fibrotic liver disease comprises liver fibrosis. In some embodiments, the fibrotic liver disease is caused by alpha-1 antitrypsin deficiency, copper storage disease, fructoseemia, galactosemia, glycogen storage disease, iron overload syndrome, dyslipidemia, Peroxisomal disorders, tyrosinemia, bacterial infections, parasitic infections, viral infections, disorders affecting hepatic blood flow, drugs or chemicals, or mechanical obstruction. In some embodiments, the fibrotic liver disease affecting hepatic blood flow is Budd-Chiari syndrome, heart failure, hepatic veno-occlusive disease, or portal vein thrombosis. In some embodiments, the drug or chemical causing fibrotic liver disease is amiodarone, chlorpromazine, isoniazid, methotrexate, methyldopa , oxyphenisatin, alcohol or tolbutamide. In some embodiments, the mechanical obstruction causing fibrotic liver disease is liver scarring due to liver surgery or bile duct stricture due to compacted gallstones.
於一些實施例中，該纖維化肝病為非酒精性脂肪性肝炎(NASH)、酒精性肝炎、原發性膽汁性膽管炎、原發性硬化性膽管炎、先天性肝纖維化或自體免疫性肝炎。 肝纖維化 In some embodiments, the fibrotic liver disease is non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, congenital liver fibrosis, or autoimmunity Hepatitis. Liver Fibrosis
肝纖維化並非獨立疾病，而是肝之組織學變化，其包含肝細胞之細胞外空間內之異常量之膠原纖維沉積。肝纖維化係由肝發炎及肝損傷引起。肝損傷引起肝星狀細胞活化以增加細胞外基質(ECM)蛋白之產生及累積，從而導致肝細胞硬化及血液輸注至肝之增加的損失。Liver fibrosis is not an independent disease, but a histological change of the liver that involves deposition of abnormal amounts of collagen fibers within the extracellular space of hepatocytes. Liver fibrosis is caused by liver inflammation and liver damage. Liver injury causes activation of hepatic stellate cells to increase the production and accumulation of extracellular matrix (ECM) proteins, leading to cirrhosis of liver cells and increased loss of blood transfusion to the liver.
於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之肝纖維化。於一些實例中，FXR促效劑減少哺乳動物之肝纖維化至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，肝纖維化減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝纖維化之程度係相對於不利用FXR促效劑治療之哺乳動物之肝纖維化之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 非酒精性脂肪性肝炎 (NASH) In some embodiments, the FXR agonists disclosed herein are used to treat liver fibrosis in mammals. In some examples, the FXR agonist reduces liver fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, liver fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of liver fibrosis is relative to the degree of liver fibrosis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. nonalcoholic steatohepatitis (NASH)
非酒精性脂肪肝病(NAFLD)係與肝中過量脂肪(脂肪變性)相關聯及於一些情況下進展為NASH，其藉由發炎、細胞死亡及纖維化之組織學特點定義。於一些實例中，原發性NASH係與胰島素抗性相關聯，而繼發性NASH係由醫療或手術狀況或藥物(諸如但不限於他莫西芬(tamoxifen))引起。於一些情況下，NASH進展為晚期纖維化、肝細胞癌或需要肝移植之末期肝病。Nonalcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (steatosis) and in some cases progresses to NASH, which is defined by histological features of inflammation, cell death and fibrosis. In some instances, primary NASH is associated with insulin resistance, while secondary NASH is caused by medical or surgical conditions or drugs such as, but not limited to, tamoxifen. In some instances, NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring liver transplantation.
於一些實例中，作為甘油三酯(TG)不平衡之結果，NASH發展。例如，功能失調脂肪細胞分泌促發炎性分子，諸如會導致胰島素抗性及脂肪細胞中之脂類分解抑制失敗之細胞激素及趨化因子。於一些實例中，此脂類分解抑制之失敗導致游離脂肪酸(FFA)釋放至循環中及於肝內攝取。於一些情況下，呈甘油三酯(TG)之形式之FFA於脂質小滴中之過度累積導致氧化壓力、粒線體功能障礙及促發炎性分子之上調。In some instances, NASH develops as a result of triglyceride (TG) imbalance. For example, dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines that lead to insulin resistance and failure of lipolytic inhibition in adipocytes. In some instances, failure of such lipolytic inhibition results in the release of free fatty acids (FFA) into the circulation and uptake in the liver. In some cases, excessive accumulation of FFA in the form of triglycerides (TG) in lipid droplets results in oxidative stress, mitochondrial dysfunction, and upregulation of pro-inflammatory molecules.
於一些實例中，FXR之活化會抑制藉由經由活化SHP抑制固醇調節元件結合蛋白1c (SREBP1c)促進之甘油三酯(TG)/脂肪酸(FA)合成。於一些情況下，FXR另外藉由刺激脂蛋白脂肪酶(LPL)活性增加TG之清除率以及藉由誘導多配體蛋白聚糖(syndecan)1 (SDC1)及VLDL受體(VLDLR)增加殘留物物及低密度脂蛋白之肝攝取。In some examples, activation of FXR inhibits triglyceride (TG)/fatty acid (FA) synthesis promoted by sterol regulatory element binding protein 1c (SREBP1c) inhibition via activation of SHP. In some cases, FXR additionally increases TG clearance by stimulating lipoprotein lipase (LPL) activity and residues by inducing syndecan 1 (SDC1) and VLDL receptor (VLDLR) and hepatic uptake of low-density lipoproteins.
習知上，NASH係使用肝活組織檢查診斷及NAFLD活動評分或NAS係用於評估嚴重度。NAS在低-至-高點量表系統上對三個類別評價及評分：(a)脂肪變性或肝脂肪(0至3)；(b)球囊擴張，其為肝細胞損傷之形式(0至2)；及(c)肝發炎(0至3)。將三個類別利用0至8之分數範圍合計，其中更高分數指示更高NASH嚴重度。除了NAS外，亦針對纖維化使用0至4階段量表評估肝組織學。0階段為無纖維化，4階段為肝硬化，及介於中間階段說明纖維化之程度在0階段與4階段之間。Conventionally, NASH is diagnosed using liver biopsy and the NAFLD activity score or NAS is used to assess severity. The NAS rates and scores three categories on a low-to-high point scale system: (a) steatosis or hepatic fat (0 to 3); (b) balloon dilatation, which is a form of hepatocyte damage (0 to 2); and (c) liver inflammation (0 to 3). The three categories were aggregated using a score range of 0 to 8, with higher scores indicating higher NASH severity. In addition to NAS, liver histology was also assessed for fibrosis using a
於一些實施例中，認為0至2之NAS分數非NASH之診斷，認為3至4之分數非診斷性，邊界線或針對NASH陽性。認為5至8之分數為NASH之診斷。In some embodiments, a NAS score of 0 to 2 is considered non-diagnostic of NASH, and a score of 3 to 4 is considered non-diagnostic, borderline, or positive for NASH. A score of 5 to 8 is considered a diagnosis of NASH.
診斷NASH及纖維化之非侵入性方法受歡迎程度增加。超音波及磁共振成像或MRI二者已顯示評估肝脂肪變性及纖維化之能力，具有高精確度。此外，亦已使用各種血液測試評估肝脂肪變性，其包括常見肝功能標誌物(諸如天冬胺酸轉胺酶或AST，及丙胺酸轉胺酶或ALT，以及纖維化之更特定標誌物)之測量值。Non-invasive methods for diagnosing NASH and fibrosis are gaining popularity. Both ultrasound and magnetic resonance imaging or MRI have shown the ability to assess hepatic steatosis and fibrosis with high accuracy. In addition, hepatic steatosis has also been assessed using various blood tests, including common markers of liver function such as aspartate transaminase or AST, and alanine transaminase or ALT, as well as more specific markers of fibrosis the measured value.
於一些實施例中，使用FIB-4評分系統評估肝纖維化。FIB-4指數經報告為簡單，精確，非侵入性且易得實驗室測試指數，其可幫助評價患有NAFLD之患者之針對肝活組織檢查之肝纖維化適應症及其他肝相關併發症之存在。FIB-4評分系統使用患者年齡、血小板計數、AST及ALT之組合。0至1.29之FIB-4分數通常指示晚期肝纖維化之低風險。1.30至2.67之FIB-4分數通常指示晚期肝纖維化之不確定風險。＞2.67之FIB-4分數通常指示晚期纖維化及發展其他肝相關事件之高風險。In some embodiments, liver fibrosis is assessed using the FIB-4 scoring system. The FIB-4 index has been reported as a simple, accurate, non-invasive and readily available laboratory test index that can aid in the evaluation of indications for liver fibrosis and other liver-related complications for liver biopsy in patients with NAFLD exist. The FIB-4 scoring system uses a combination of patient age, platelet count, AST and ALT. A FIB-4 score of 0 to 1.29 generally indicates a low risk of advanced liver fibrosis. FIB-4 scores of 1.30 to 2.67 generally indicate an uncertain risk of advanced liver fibrosis. A FIB-4 score >2.67 generally indicates a high risk of advanced fibrosis and development of other liver-related events.
於一些實施例中，向患有肝纖維化之哺乳動物投與化合物1或其醫藥上可接受之鹽引起肝纖維化之消退。於一些實施例中，該肝纖維化之消退於每日投與化合物1或其醫藥上可接受之鹽約2週、約4週、約6週、約8週、約10週、約12週、約14週、約16週、約18週、約20週、約24週、約26週、約52週、或超過約52週後注意到。In some embodiments, administration of
於一些實施例中，纖維化之消退經定義為成對連續量測中之纖維化評分之減少，無論使用哪種評分系統。纖維化分數之差異用作評價各種藥物之效應之臨床試驗的組織學結果。In some embodiments, regression of fibrosis is defined as a decrease in the fibrosis score in paired serial measurements, regardless of the scoring system used. Differences in fibrosis scores were used as histological findings in clinical trials evaluating the effects of various drugs.
於一些實施例中，纖維化之消退經定義為FIB-4分數之減少。於一些實施例中，FIB-4分數減少至少0.5、1、1.5、2或大於2。In some embodiments, regression of fibrosis is defined as a reduction in FIB-4 score. In some embodiments, the FIB-4 score is reduced by at least 0.5, 1, 1.5, 2, or greater than 2.
於一些實施例中，利用FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)治療NASH包括NAS分數減少1、2、3、4、5、6、7或8。於一些實施例中，NAS分數之減少於每日投與化合物1或其醫藥上可接受之鹽約2週、約4週、約6週、約8週、約10週、約12週、約14週、約16週、約18週、約20週、約24週、約26週、約52週、或超過約52週後注意到。In some embodiments, treatment of NASH with an FXR agonist (eg,
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療NASH包括肝脂肪減少、肝纖維化減少、肝組織學改善、肝血液測試改善、膽汁鬱積性搔癢改善或其組合。In some embodiments, treatment of NASH with
於一些實施例中，將結果量度與對照相比。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之個體。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之全劑量之個體。於一些實施例中，對照為針對在接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之前之個體之基線。In some embodiments, the outcome measure is compared to a control. In some embodiments, the controls are subjects that do not receive an FXR agonist (eg,
於一些實施例中，結果量度於每日投與化合物1或其醫藥上可接受之鹽約2週、約4週、約6週、約8週、約10週、約12週、約14週、約16週、約18週、約20週、約24週、約26週、約52週、或超過約52週後獲得。In some embodiments, the outcome measure is about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks of daily administration of
於一些實施例中，於投與化合物1或其醫藥上可接受之鹽後獲得自基線約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%或更大之肝脂肪減少。In some embodiments, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% from baseline after administration of
於一些實施例中，肝纖維化之減少包括肝纖維化分數自基線減少至少1、至少2、至少3或更多。In some embodiments, the reduction in liver fibrosis comprises a reduction in liver fibrosis score of at least 1, at least 2, at least 3, or more from baseline.
於一些實施例中，肝血液測試包括量測丙胺酸轉胺酶(ALT)含量、天冬胺酸轉胺酶(AST)含量、γ-麩胺醯基轉移酶(GGT)、甘油三酯(TG)含量、總膽固醇含量、高密度脂蛋白(HDL)含量、低密度脂蛋白(LDL)含量或其組合。In some embodiments, the liver blood test includes measuring alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, gamma-glutaminyltransferase (GGT), triglycerides ( TG) content, total cholesterol content, high density lipoprotein (HDL) content, low density lipoprotein (LDL) content, or a combination thereof.
於由於NAFLD之肝脂肪變性中通常觀察到之生物化學模式為增加之轉胺酶含量，其中丙胺酸轉胺酶(ALT)含量超過天冬胺酸轉胺酶(AST)之彼等。然而，隨著肝脂肪變性進展為NASH及相關肝纖維化，AST含量增加，從而導致隨著AST:ALT比率增加。於一些實施例中，GGT含量沿著轉胺酶之NAFLD模式增加。於一些實施例中，顯示ALT及GGT二者均與超音波掃描術上之脂肪肝之存在及與如由磁共振成像光譜所量測之肝脂肪含量適度相關聯，然而AST係不相關。The biochemical pattern commonly observed in hepatic steatosis due to NAFLD is increased transaminase levels, with alanine transaminase (ALT) levels exceeding those of aspartate transaminase (AST). However, as hepatic steatosis progresses to NASH and related hepatic fibrosis, AST content increases, resulting in increased AST:ALT ratios. In some embodiments, the GGT content increases along the NAFLD pattern of the transaminase. In some embodiments, both ALT and GGT were shown to correlate modestly with the presence of fatty liver on ultrasonography and with liver fat content as measured by magnetic resonance imaging spectroscopy, whereas AST was not.
於一些實施例中，ALT含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。於一些實施例中，AST含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。於一些實施例中，GGT含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。於一些實施例中，TG含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。於一些實施例中，HDL含量自基線增加至少10%、至少20%、至少30%、至少40%、至少50%或更多。於一些實施例中，LDL含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。In some embodiments, ALT levels are reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some embodiments, AST levels are reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some embodiments, the GGT content is reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some embodiments, the TG content is reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some embodiments, HDL levels are increased from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some embodiments, the LDL content is reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。原發性膽汁性膽管炎 (PBC) In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Primary Biliary Cholangitis (PBC)
PBC為主要自將膽汁酸(BA)運送出肝之膽管之自體免疫性破壞產生之肝病，該破壞導致膽汁鬱積。隨著PBC進展，BA之持久毒性積聚引起進行性肝損傷。慢性發炎及纖維化進展為肝硬化。PBC為慢性進行性病症，其症狀通常於中年發展。PBC之目前治療包括熊去氧膽酸(UDCA)。亦已探索其他FXR促效劑作為潛在療法。增加之FXR活性與減少之膽汁酸合成相關，其可減輕與PBC相關聯之肝中之膽汁酸的積聚。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之原發性膽汁性膽管炎(PBC)。於一些實例中，FXR促效劑減少哺乳動物之PBC至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，PBC減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，PBC之程度係相對於不利用FXR促效劑治療之哺乳動物之PBC之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 原發性硬化性膽管炎 (PSC) PBC is a liver disease that arises primarily from autoimmune destruction of the bile ducts that transport bile acids (BA) out of the liver, resulting in cholestasis. The persistent toxic accumulation of BA causes progressive liver damage as PBC progresses. Chronic inflammation and fibrosis progress to cirrhosis. PBC is a chronic progressive disorder whose symptoms usually develop in middle age. Current treatments for PBC include ursodeoxycholic acid (UDCA). Other FXR agonists have also been explored as potential therapies. Increased FXR activity is associated with decreased bile acid synthesis, which reduces bile acid accumulation in the liver associated with PBC. In some embodiments, the FXR agonists disclosed herein are used to treat primary biliary cholangitis (PBC) in mammals. In some examples, the FXR agonist reduces PBC in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the PBC is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of PBC is relative to the degree of PBC in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Primary sclerosing cholangitis (PSC)
PSC為慢性及進行性膽汁鬱積肝病。PSC之特徵在於進行性發炎、纖維化及肝管狹窄形成。常見症狀包括搔癢及黃疸。該疾病與發炎性腸病(IBD)強烈相關聯；患有潰瘍性結腸炎之患者之約5%將患有PSC。患有PSC之患者之至多70%亦患有IBD，最常見潰瘍性結腸炎。於一些實施例中，本文中所揭示之FXR促效劑係用於治療原發性硬化性膽管炎(PSC)。於一些實例中，FXR促效劑減少哺乳動物之PSC至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，PSC減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，PSC之程度係相對於不利用FXR促效劑治療之哺乳動物之PSC之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 先天性或新生兒肝病 PSC is a chronic and progressive cholestatic liver disease. PSC is characterized by progressive inflammation, fibrosis, and hepatic duct stricture formation. Common symptoms include itching and jaundice. The disease is strongly associated with inflammatory bowel disease (IBD); approximately 5% of patients with ulcerative colitis will have PSC. Up to 70% of patients with PSC also have IBD, most commonly ulcerative colitis. In some embodiments, the FXR agonists disclosed herein are used to treat primary sclerosing cholangitis (PSC). In some examples, the FXR agonist reduces PSC in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the PSC is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of PSC is relative to the extent of PSC in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Congenital or neonatal liver disease
先天性或新生兒肝病包括(但不限於)先天性肝纖維化、膽道閉鎖、阿拉吉歐症候群、進行性家族性肝內膽汁鬱積-1 (PFIC-1)、PFIC-2、PFIC-3、α-1抗胰蛋白酶缺乏、總膽管囊腫及威爾森氏病。於一些實施例中，先天性或新生兒肝病為孤兒肝病。Congenital or neonatal liver diseases including (but not limited to) congenital hepatic fibrosis, biliary atresia, Alageo syndrome, progressive familial intrahepatic cholestasis-1 (PFIC-1), PFIC-2, PFIC-3 , alpha-1 antitrypsin deficiency, choledochal cyst and Wilson's disease. In some embodiments, the congenital or neonatal liver disease is an orphan liver disease.
先天性肝纖維化為與門靜脈及膽管之異常發育及導致門靜脈高壓之門靜脈週纖維化相關聯之罕見遺傳病。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之先天性肝纖維化。於一些實例中，FXR促效劑減少哺乳動物之先天性肝纖維化至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，先天性肝纖維化減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，先天性肝纖維化之程度係相對於不利用FXR促效劑治療之哺乳動物之先天性肝纖維化之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 Congenital hepatic fibrosis is a rare genetic disease associated with abnormal development of the portal vein and bile duct and periportal fibrosis leading to portal hypertension. In some embodiments, the FXR agonists disclosed herein are used to treat congenital liver fibrosis in mammals. In some examples, the FXR agonist reduces congenital liver fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the congenital liver fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of congenital liver fibrosis is relative to the degree of congenital liver fibrosis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
膽道閉鎖(亦稱作肝外導管減少症或進行性閉塞性膽管病)為於嬰兒中出現之罕見醫療病狀，其中膽管在出生之前發育異常及因此於出生後變得發炎及/或阻塞。此阻塞導致膽汁酸及可引起肝損傷之其他化合物之積聚。該病狀影響約1/15,000嬰兒。膽道閉鎖之症狀包括黃疸、尿色深、酒精性糞便、體重損失及過敏性。患有該疾病之兒童不可適當消化脂肪及可遭受維生素或蛋白質之損失。未經治療，該病狀可導致死亡。目前不存在治療膽道閉鎖之藥劑，其中需要手術用於治療。患有膽道閉鎖之個體顯示血液及血漿中之升高之膽汁酸含量。此外，患有膽道閉鎖之患者亦顯示FXR之減少之表現。增加之FXR活性與減少之膽汁酸合成相關，其可減輕與膽道閉鎖相關聯之肝中之膽汁酸之積聚。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之膽道閉鎖。於一些實例中，FXR促效劑減少哺乳動物之膽道閉鎖至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，膽道閉鎖減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，膽道閉鎖之程度係相對於不利用FXR促效劑治療之哺乳動物之膽道閉鎖之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Biliary atresia (also known as extrahepatic ductal reduction or progressive obliterative cholangiopathies) is a rare medical condition in infants in which the bile ducts develop abnormally before birth and thus become inflamed and/or blocked after birth . This blockage results in the accumulation of bile acids and other compounds that can cause liver damage. The condition affects about 1 in 15,000 babies. Symptoms of biliary atresia include jaundice, dark urine, alcoholic stools, weight loss, and allergies. Children with this disease cannot properly digest fats and can suffer vitamin or protein losses. Without treatment, the condition can lead to death. There is currently no medication for the treatment of biliary atresia, in which surgery is required for treatment. Individuals with biliary atresia show elevated bile acid levels in blood and plasma. In addition, patients with biliary atresia also showed a reduction in FXR. Increased FXR activity correlates with decreased bile acid synthesis, which reduces the accumulation of bile acids in the liver associated with biliary atresia. In some embodiments, the FXR agonists disclosed herein are used to treat biliary atresia in mammals. In some examples, the FXR agonist reduces biliary atresia in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, biliary atresia is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of biliary atresia is relative to the degree of biliary atresia in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
阿拉吉歐症候群為常染色體顯性遺傳病，其尤其導致膽管發育不良、膽汁缺乏或膽道閉鎖之所致病狀。於阿拉吉歐症候群中，膽管異常導致降低之將膽汁酸運送出肝之能力。此導致膽汁酸於肝中積聚，其可引起防止肝適當工作之瘢痕。阿拉吉歐症候群之症狀之治療包括投與熊去氧膽酸，一種證明幫助膽汁流出肝之FXR促效劑。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之阿拉吉歐症候群。於一些實例中，FXR促效劑減少哺乳動物之阿拉吉歐症候群至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，阿拉吉歐症候群減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，阿拉吉歐症候群之程度係相對於不利用FXR促效劑治療之哺乳動物之阿拉吉歐症候群之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Alaggio Syndrome is an autosomal dominant disorder that results in, inter alia, bile duct dysplasia, bile deficiency, or biliary atresia. In Alaggio syndrome, bile duct abnormalities result in a reduced ability to transport bile acids out of the liver. This causes bile acids to build up in the liver, which can cause scarring that prevents the liver from working properly. Treatment of the symptoms of Alageo syndrome involves administration of ursodeoxycholic acid, an FXR agonist shown to aid bile flow out of the liver. In some embodiments, the FXR agonists disclosed herein are used to treat Alaggio Syndrome in mammals. In some examples, the FXR agonist reduces Alaggio syndrome in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, Alageo syndrome is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of Alageo Syndrome is relative to the extent of Alageo Syndrome in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
進行性家族性肝內膽汁鬱積(PFIC)為引起嬰兒及年輕人之進行性膽汁鬱積之遺傳病之群，其導致肝硬化及最終需要肝移植。存在PFIC之三種變型：PFIC-1、PFIC-2及PFIC-3。PFIC-1係由ATP8B1 (編碼FIC-1之基因)之突變引起，該基因負責磷脂跨膜轉位。PFIC-2係由ABCB11 (編碼膽鹽輸出泵(BSEP)之基因)之突變引起。PFIC-3係由ABCB4 (編碼耐多種藥物性蛋白3 (MDR3)之基因)之突變引起，該基因負責磷脂醯膽鹼轉位。因為PFIC係與肝中之膽汁酸之積聚相關聯，已探索FXR促效劑作為PFIC之潛在療法。已於動物模型中看到一些成功，但是接受治療之患者看到血脂異常頻率增加反應。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之PFIC或其變型中之任一者。於一些實例中，FXR促效劑減少哺乳動物之PFIC或其變型中之任一者至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，PFIC或其變型中之任一者減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，PFIC或其變型中之任一者之程度係相對於不利用FXR促效劑治療之哺乳動物之PFIC之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders that cause progressive cholestasis in infants and young adults, which leads to cirrhosis of the liver and ultimately requires liver transplantation. There are three variants of PFIC: PFIC-1, PFIC-2 and PFIC-3. PFIC-1 is caused by mutations in ATP8B1, the gene encoding FIC-1, which is responsible for translocation of phospholipids across membranes. PFIC-2 is caused by mutations in ABCB11, the gene encoding the bile salt export pump (BSEP). PFIC-3 is caused by mutations in ABCB4, the gene encoding multidrug resistance protein 3 (MDR3), which is responsible for phosphocholine translocation. Because PFIC is associated with the accumulation of bile acids in the liver, FXR agonists have been explored as potential treatments for PFIC. Some success has been seen in animal models, but treated patients see an increased frequency of dyslipidemia responses. In some embodiments, the FXR agonists disclosed herein are used to treat PFIC in mammals or any of its variants. In some examples, the FXR agonist reduces PFIC in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or More. In some cases, PFIC or any of its variants is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of PFIC or any of its variants is relative to the degree of PFIC in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
α-1抗胰蛋白酶缺乏為引起α-1抗胰蛋白酶(A1AT)之缺陷產生之遺傳病狀，其導致A1AT於肝中累積。A1AT缺乏導致許多疾病，包括(但不限於)肝硬化、自體免疫性肝炎、慢性阻塞性肺病(COPD)、哮喘或肺氣腫。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之A1AT缺乏。於一些實例中，FXR促效劑減少哺乳動物之A1AT缺乏至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，A1AT缺乏減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，A1AT缺乏之程度係相對於不利用FXR促效劑治療之哺乳動物之A1AT缺乏之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Alpha-1 antitrypsin deficiency is a genetic condition that causes defective production of alpha-1 antitrypsin (A1AT), which results in the accumulation of A1AT in the liver. A1AT deficiency leads to many diseases including, but not limited to, liver cirrhosis, autoimmune hepatitis, chronic obstructive pulmonary disease (COPD), asthma or emphysema. In some embodiments, the FXR agonists disclosed herein are used to treat A1AT deficiency in mammals. In some examples, the FXR agonist reduces A1AT deficiency in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the A1AT deficiency is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the degree of A1AT deficiency is relative to the degree of A1AT deficiency in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
總膽管囊腫為涉及膽管囊性擴張之先天性病狀，其進一步發展呈膽管炎。總膽管囊腫分成：I型、II型、III型或總膽管囊腫IVa型、IVb型、V型及VI型。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之總膽管囊腫。於一些實例中，FXR促效劑減少哺乳動物之總膽管囊腫至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，總膽管囊腫減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Choledochocyst is a congenital condition involving cystic dilatation of the bile duct, which further develops as cholangitis. Choledochal cysts are divided into: I, II, III or choledochal cysts IVa, IVb, V and VI. In some embodiments, the FXR agonists disclosed herein are used to treat choledochal cysts in mammals. In some examples, the FXR agonist reduces choledochal cysts in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the choledochocyst is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
威爾森氏病為常染色體隱性病狀，其中銅未自身體適當***。威爾森氏病之症狀通常影響腦及肝。威爾森氏病之併發症包括(但不限於)肝性腦病、門靜脈高壓、慢性肝炎、急性肝衰竭、溶血性貧血及脾腫大。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之威爾森氏病或威爾森氏病之併發症。於一些實例中，FXR促效劑及附加治療劑減少哺乳動物之威爾森氏病或威爾森氏病之併發症至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，威爾森氏病或威爾森氏病之併發症減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。自體免疫性肝炎 Wilson's disease is an autosomal recessive condition in which copper is not properly excreted from the body. Symptoms of Wilson's disease usually affect the brain and liver. Complications of Wilson's disease include, but are not limited to, hepatic encephalopathy, portal hypertension, chronic hepatitis, acute liver failure, hemolytic anemia, and splenomegaly. In some embodiments, the FXR agonists disclosed herein are used to treat Wilson's disease or complications of Wilson's disease in mammals. In some examples, the FXR agonist and the additional therapeutic agent reduce Wilson's disease or complications of Wilson's disease in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% , at least 40%, at least 50% or more. In some instances, Wilson's disease or complications of Wilson's disease are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. autoimmune hepatitis
自體免疫性肝炎為特徵在於慢性肝發炎及壞死之慢性自體免疫性疾病，其導致肝硬化。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之自體免疫性肝炎。於一些實例中，FXR促效劑減少哺乳動物之自體免疫性肝炎至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，自體免疫性肝炎減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，自體免疫性肝炎之程度係相對於不利用FXR促效劑治療之哺乳動物之自體免疫性肝炎之程度。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。其他肝臟疾病或病狀 Autoimmune hepatitis is a chronic autoimmune disease characterized by chronic liver inflammation and necrosis, which leads to cirrhosis. In some embodiments, the FXR agonists disclosed herein are used to treat autoimmune hepatitis in mammals. In some examples, the FXR agonist reduces autoimmune hepatitis in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the autoimmune hepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the extent of autoimmune hepatitis is relative to the extent of autoimmune hepatitis in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. other liver diseases or conditions
於一些實施例中，本文中所揭示之FXR促效劑係用於治療、預防或減慢哺乳動物之末期肝病之進展。於一些實例中，FXR促效劑減少哺乳動物之末期肝症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，末期肝症狀減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，末期肝病之進展係相對於不利用FXR促效劑治療之哺乳動物之末期肝病之進展。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some embodiments, the FXR agonists disclosed herein are used to treat, prevent or slow the progression of end-stage liver disease in mammals. In some examples, the FXR agonist reduces end-stage liver symptoms in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some examples, end-stage liver symptoms are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the progression of end-stage liver disease is relative to the progression of end-stage liver disease in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
肝細胞癌為最常見類型之肝癌，其經常於患有慢性肝病(諸如B型肝炎或C型肝炎)之人中出現。於許多情況下，FXR表現及信號傳導於肝細胞癌患者中下調。鑑於FXR於控制膽汁酸代謝、抑制發炎信號傳導及增強組織修復中起作用，假設FXR於預防肝癌發生中起著重要作用。此外，研究已顯示癌細胞經FXR促效劑治療導致細胞生長抑制。於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之肝細胞癌。於一些實例中，FXR促效劑減少哺乳動物之肝細胞癌症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，肝細胞癌症狀減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝細胞癌之進展係相對於不利用FXR促效劑治療之哺乳動物之肝細胞癌之進展。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。Hepatocellular carcinoma is the most common type of liver cancer and occurs frequently in people with chronic liver disease such as hepatitis B or C. In many cases, FXR expression and signaling are downregulated in hepatocellular carcinoma patients. Given that FXR plays a role in controlling bile acid metabolism, inhibiting inflammatory signaling, and enhancing tissue repair, it is hypothesized that FXR plays an important role in the prevention of hepatocarcinogenesis. In addition, studies have shown that treatment of cancer cells with FXR agonists results in cell growth inhibition. In some embodiments, the FXR agonists disclosed herein are used to treat hepatocellular carcinoma in mammals. In some examples, the FXR agonist reduces hepatocellular carcinoma symptoms in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some examples, hepatocellular carcinoma symptoms are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the progression of hepatocellular carcinoma is relative to the progression of hepatocellular carcinoma in a mammal not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之肝酶。於一些實例中，FXR促效劑減少哺乳動物之肝酶(例如，血清ALT及/或AST含量)至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，肝酶之含量減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝酶之含量係相對於不利用FXR促效劑治療之哺乳動物之肝酶之含量。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some embodiments, the FXR agonists disclosed herein reduce mammalian liver enzymes. In some examples, the FXR agonist reduces liver enzymes (eg, serum ALT and/or AST levels) in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more. In some examples, the level of liver enzymes is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the levels of liver enzymes are relative to the levels of liver enzymes in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一些實施例中，本文中所揭示之FXR促效劑減少哺乳動物之肝甘油三酯。於一些實例中，FXR促效劑減少哺乳動物之肝甘油三酯至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些實例中，肝甘油三酯之含量減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實例中，肝甘油三酯之含量係相對於不利用FXR促效劑治療之哺乳動物之肝甘油三酯之含量。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。膽管癌 In some embodiments, the FXR agonists disclosed herein reduce hepatic triglycerides in mammals. In some examples, the FXR agonist reduces hepatic triglycerides by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more in the mammal. In some examples, the level of hepatic triglycerides is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some examples, the levels of hepatic triglycerides are relative to the levels of hepatic triglycerides in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Cholangiocarcinoma
膽管癌為於個體之膽管中形成之一種癌症。雖然不清楚什麼引起導致此癌症之遺傳突變，但是風險因素包括原發性硬化性膽管炎、慢性肝病、及其他膽管問題。發炎及膽汁鬱積為形成膽管癌之關鍵因素。膽管癌藉由其於肝中之位置分類。肝內膽管癌(該等疾病之最不常見形式)於肝內之小膽管中開始。門周膽管癌(亦稱作Klatskin瘤)於門(其中兩個主要膽管連接及離開肝之區域)中開始。門周膽管癌為該疾病之最常見形式。膽管癌之其他形式稱作遠側膽管癌，其於肝外之膽管中開始。Cholangiocarcinoma is a type of cancer that forms in the bile ducts of an individual. Although it is unclear what genetic mutations cause this cancer, risk factors include primary sclerosing cholangitis, chronic liver disease, and other bile duct problems. Inflammation and cholestasis are key factors in the development of cholangiocarcinoma. Cholangiocarcinomas are classified by their location in the liver. Intrahepatic cholangiocarcinoma, the least common form of these diseases, begins in the small bile ducts within the liver. Periportal cholangiocarcinoma (also known as Klatskin tumor) begins in the hilum, the area where the two main bile ducts join and leave the liver. Periportal cholangiocarcinoma is the most common form of the disease. Another form of cholangiocarcinoma, called distal cholangiocarcinoma, begins in the bile ducts outside the liver.
膽汁酸可活化表皮生長因子受體(EGFR)及增強環氧酶2 (COX-2)表現。COX-2異常調節膽管癌之生長，增強細胞凋亡抗性，及積極調節促致癌信號路徑，諸如肝細胞生長因子、IL-6及EGFR，因此指示膽汁酸含量與膽管癌之發病率及進展之間之潛在聯繫。Bile acids activate epidermal growth factor receptor (EGFR) and enhance cyclooxygenase 2 (COX-2) expression. COX-2 dysregulates cholangiocarcinoma growth, enhances apoptosis resistance, and positively regulates pro-oncogenic signaling pathways such as hepatocyte growth factor, IL-6, and EGFR, thus indicating bile acid content and cholangiocarcinoma incidence and progression potential connection between them.
FXR表現於膽管癌細胞中與健康膽管細胞相比下調。研究已顯示人類肝內膽管癌細胞與FXR促效劑奧貝膽酸(obeticholic acid)之培養物之治療可加強FXR於活體外表現。經FXR促效劑治療之膽管癌細胞顯示減少之增殖及增加之細胞凋亡。FXR is downregulated in cholangiocarcinoma cells compared to healthy cholangiocarcinoma cells. Studies have shown that treatment of cultures of human intrahepatic cholangiocarcinoma cells with the FXR agonist obeticholic acid enhances FXR expression in vitro. Cholangiocarcinoma cells treated with FXR agonists showed decreased proliferation and increased apoptosis.
於一些實施例中，本文中所揭示之FXR促效劑係用於治療哺乳動物之膽管癌。於一些實施例中，該膽管癌為肝內膽管癌。於一些實施例中，該膽管癌為門周膽管癌。於一些實施例中，該膽管癌為遠側膽管癌。於一些實施例中，經FXR促效劑治療減少膽管癌細胞之增殖至少10%、至少20%、至少30%、至少40%或至少50%。於一些實施例中，經FXR促效劑治療增加膽管癌細胞之細胞凋亡至少10%、至少20%、至少30%、至少40%或至少50%。於一些實施例中，經FXR促效劑治療增加膽管癌細胞之FXR表現至少10%、至少20%、至少30%、至少40%或至少50%。In some embodiments, the FXR agonists disclosed herein are used to treat cholangiocarcinoma in mammals. In some embodiments, the cholangiocarcinoma is intrahepatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is periportal cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is distal cholangiocarcinoma. In some embodiments, FXR agonist treatment reduces proliferation of cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, FXR agonist treatment increases apoptosis in cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, FXR agonist treatment increases FXR expression of cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.
於一個態樣中，本文中描述一種治療或預防哺乳動物之肝臟疾病或病狀之方法，其包括向該哺乳動物投與本文中所揭示之FXR促效劑，單獨或與其他治療劑組合。於一些實施例中，該肝臟疾病或病狀為纖維化肝病、代謝性肝病、孤兒肝病或其任何組合。 胃腸疾病 In one aspect, described herein is a method of treating or preventing a liver disease or condition in a mammal comprising administering to the mammal an FXR agonist disclosed herein, alone or in combination with other therapeutic agents. In some embodiments, the liver disease or condition is fibrotic liver disease, metabolic liver disease, orphan liver disease, or any combination thereof. Gastrointestinal disease
於某些實施例中，本文中揭示治療或預防有需要個體之胃腸疾病之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑。於一些實施例中，該胃腸疾病與肝病相關聯。於一些實施例中，該胃腸疾病與纖維化肝病相關聯。於一些實施例中，該胃腸疾病與代謝性肝病相關聯。於一些實施例中，該胃腸疾病為大腸激躁症候群(IBS)、大腸激躁症候群伴腹瀉(IBS-D)、大腸激躁症候群伴便秘(IBS-C)、混合型IBS (IBS-M)、未分亞型之IBS (IBS-U)或膽汁酸腹瀉(BAD)。於一些實施例中，該胃腸疾病為膽汁酸吸收不良、移植物抗宿主疾病、克羅恩氏病、發炎性腸病、壞死性小腸結腸炎、胃炎、潰瘍性結腸炎、胃腸炎、輻射誘導之腸炎、假膜性結腸炎、化療誘導之腸炎、胃食道逆流疾病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸乳糜瀉、手術後發炎、胃腸癌形成或其任何組合。大腸激躁症候群 In certain embodiments, disclosed herein are methods of treating or preventing a gastrointestinal disorder in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist. In some embodiments, the gastrointestinal disease is associated with liver disease. In some embodiments, the gastrointestinal disease is associated with fibrotic liver disease. In some embodiments, the gastrointestinal disease is associated with metabolic liver disease. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M) , Unsubtyped IBS (IBS-U) or bile acid diarrhea (BAD). In some embodiments, the gastrointestinal disease is bile acid malabsorption, graft-versus-host disease, Crohn's disease, inflammatory bowel disease, necrotizing enterocolitis, gastritis, ulcerative colitis, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced colitis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, celiac disease, post-operative inflammation, gastrointestinal cancer or any combination thereof. irritable bowel syndrome
大腸激躁症候群(IBS)為包含腹痛及腸運動模式之變化之症狀之組合，其持續延長之時間段，通常幾年。IBS之原因仍不清楚；然而，認為腸運動問題、食物敏感性、遺傳因素、小腸細菌過度生長、及腸-腦軸問題具有潛在作用。於一些實例中，IBS伴隨腹瀉及分類為IBS伴隨腹瀉(IBS-D)。於一些實例中，IBS伴隨便秘及分類為IBS伴便秘(IBS-C)。於一些實例中，IBS伴腹瀉及便秘之交替模式及分類為混合型IBS (IBS-M)。於一些實例中，IBS不伴腹瀉或便秘及分類為未分亞型之IBS (IBS-U)。於一些實例中，IBS具有四個不同變型：IBS-D、IBS-C、IBS-M及IBS-U。Irritable Bowel Syndrome (IBS) is a combination of symptoms involving abdominal pain and changes in bowel movement patterns that persist for an extended period of time, usually several years. The cause of IBS remains unclear; however, bowel motility problems, food sensitivities, genetic factors, small intestinal bacterial overgrowth, and problems with the gut-brain axis are believed to have potential roles. In some instances, IBS with diarrhea and is classified as IBS with diarrhea (IBS-D). In some instances, IBS with constipation is classified as IBS with constipation (IBS-C). In some instances, the alternating pattern and classification of IBS with diarrhea and constipation is mixed IBS (IBS-M). In some instances, IBS is not associated with diarrhea or constipation and is classified as IBS of Unsubtyped (IBS-U). In some examples, IBS has four different variants: IBS-D, IBS-C, IBS-M, and IBS-U.
於一些實施例中，IBS之症狀由不同病狀模仿。於一些實施例中，糖消化不良、乳糜瀉、無乳糜瀉之麩質不耐受、胰外分泌不足、小腸細菌過度生長、顯微鏡性結腸炎或膽汁酸吸收不良(BAM)模擬IBS-D。於一些實施例中，肛門痙攣、骨盆底協同失調或直腸痙攣、或會陰下降症候群模擬IBS-C。於一些實施例中，某些病狀促進患有IBS之患者之症狀。於一些實施例中，某些病狀為患有IBS之患者之症狀之主要貢獻者。於一些實施例中，此等病狀之非限制性實例為：糖消化不良、乳糜瀉、無乳糜瀉之麩質不耐受、胰外分泌不足、小腸細菌過度生長、顯微鏡性結腸炎、膽汁酸吸收不良(BAM)、肛門痙攣、骨盆底協同失調或直腸痙攣、或會陰下降症候群。In some embodiments, the symptoms of IBS are mimicked by different conditions. In some embodiments, sugar indigestion, celiac disease, gluten intolerance without celiac disease, exocrine pancreatic insufficiency, small intestinal bacterial overgrowth, microscopic colitis, or bile acid malabsorption (BAM) mimics IBS-D. In some embodiments, anal spasm, pelvic floor dyssynergy or rectal spasm, or perineal descent syndrome mimics IBS-C. In some embodiments, certain conditions promote symptoms in patients with IBS. In some embodiments, certain pathologies are major contributors to symptoms in patients with IBS. In some embodiments, non-limiting examples of such conditions are: sugar indigestion, celiac disease, gluten intolerance without celiac disease, exocrine pancreatic insufficiency, small intestinal bacterial overgrowth, microscopic colitis, bile acids Malabsorption (BAM), anal spasm, pelvic floor dyssynergia or rectal spasm, or perineal descent syndrome.
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之IBS或其變型中之任一者。於一些實例中，FXR促效劑減少哺乳動物之由IBS或其變型中之任一者引起之症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，IBS或其變型中之任一者減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。膽汁酸吸收不良 In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein for the treatment of IBS in a mammal or any of its variants. In some examples, the FXR agonist reduces symptoms caused by IBS or any of its variants in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more. In some cases, IBS or any of its variants is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Bile acid malabsorption
膽汁酸吸收不良(BAM)，亦稱作膽汁酸腹瀉(BAD)、膽汁酸誘導之腹瀉、膽汁溢出性或促膽汁性腸病、或膽鹽吸收不良，為其中膽汁酸於結腸中之存在引起腹瀉之病狀。BAM係由許多病狀，諸如克羅恩氏病、膽囊切除術、乳糜瀉、放射療法及胰疾病引起。於一些實例中，BAM係特發性。於一些實例中，BAM係由藥劑(甲福明(metformin))引起。Bile acid malabsorption (BAM), also known as bile acid diarrhea (BAD), bile acid-induced diarrhea, bile overflow or biliary enteropathy, or bile salt malabsorption, caused by the presence of bile acids in the colon Symptoms of diarrhea. BAM is caused by many conditions such as Crohn's disease, cholecystectomy, celiac disease, radiation therapy, and pancreatic disease. In some instances, BAM is idiopathic. In some instances, BAM is caused by an agent (metformin).
於一些實施例中，BAM係由膽汁酸之過度產生引起。膽汁酸合成由回腸激素纖維母細胞生長因子19 (FGF-19)負調節；FGF-19之低含量導致膽汁酸之增加。FXR活化促進FGF-19之合成，因此降低膽汁酸之含量。膽汁酸合成亦藉由血清7α-羥基-4-膽烯-3-酮(C4)含量(肝中膽汁酸合成之標誌物)調節。C4隨著FXR活化減少。更高C4含量及因此更高膽汁酸含量於BAM患者中見到。In some embodiments, BAM is caused by overproduction of bile acids. Bile acid synthesis is negatively regulated by the ileal hormone fibroblast growth factor 19 (FGF-19); low levels of FGF-19 lead to an increase in bile acids. FXR activation promotes FGF-19 synthesis, thereby reducing bile acid levels. Bile acid synthesis is also regulated by serum 7α-hydroxy-4-cholen-3-one (C4) levels, a marker of bile acid synthesis in the liver. C4 decreases with FXR activation. Higher C4 levels and thus higher bile acid levels were seen in BAM patients.
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療BAM包括增加血清FGF-19含量、減少血清C4含量、BAM之一或多種臨床症狀之改善或其組合。In some embodiments, treating BAM with
於一些實施例中，血清FGF-19含量自基線增加至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、或大於90%。於一些實施例中，血清FGF-19含量自基線增加至少100%或更多。In some embodiments, serum FGF-19 levels increase from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or greater than 90%. In some embodiments, serum FGF-19 levels are increased by at least 100% or more from baseline.
於一些實施例中，血清C4含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。In some embodiments, serum C4 levels are reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
BAM之臨床症狀包括(但不限於)增加之糞便頻率、減少之糞便形式(例如，腹瀉)、腹痛及氣脹。Clinical symptoms of BAM include, but are not limited to, increased stool frequency, decreased stool pattern (eg, diarrhea), abdominal pain, and gas.
一或多種臨床症狀之改善係與對照相比。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之個體。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之全劑量之個體。於一些實施例中，對照為針對在接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之前之個體之基線。Improvement in one or more clinical symptoms is compared to a control. In some embodiments, the controls are subjects that do not receive an FXR agonist (eg,
於一些實施例中，一或多種臨床症狀之改善於每日投與化合物1或其醫藥上可接受之鹽約2週、約4週、約6週、約8週、約10週、約12週、約14週、約16週、約18週、約20週、約24週、約26週、約52週、或超過約52週後獲得。In some embodiments, the improvement of one or more clinical symptoms is about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks of daily administration of
BAM之一或多種臨床症狀之改善包括糞便頻率減少、糞便形式改善、腹痛減少、氣脹減少或其組合。Improvement in one or more clinical symptoms of BAM includes decreased stool frequency, improved stool pattern, decreased abdominal pain, decreased bloating, or a combination thereof.
於一些實施例中，糞便頻率減少包括少1次糞便/天、少2次糞便/天、少3次糞便/天、少4次糞便/天、少5次糞便/天、少6次糞便/天、或少超過6次糞便/天。In some embodiments, the reduction in stool frequency includes 1 less stool/day, 2 fewer stools/day, 3 fewer stools/day, 4 fewer stools/day, 5 fewer stools/day, 6 fewer stools/day day, or less than 6 stools/day.
於一些實施例中，臨床症狀改善以按照Bristol糞便量表之糞便類型自基線之變化量測。該Bristol糞便量表為經設計以在根據漸增稀薄度在1至7之量表上將糞便分類的醫療輔助。In some embodiments, clinical improvement is measured as a change from baseline in stool type on the Bristol stool scale. The Bristol stool scale is a medical aid designed to classify stool on a scale of 1 to 7 according to increasing thinning.
於一些實施例中，腹痛在WAP疼痛量表上自基線改善至少1點、至少2點、至少3點、至少4點、至少5點或超過5點。In some embodiments, the abdominal pain is improved by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or more than 5 points from baseline on the WAP pain scale.
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之BAM。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少膽汁酸合成。於一些實施例中，本文中所揭示之FXR促效劑減少膽汁酸含量。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以預防BAM。於一些實例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少哺乳動物之BAM症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，BAM減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，向該哺乳動物投與附加治療劑。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 移植物抗宿主疾病 (GvHD) In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat BAM in a mammal. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce bile acid synthesis. In some embodiments, the FXR agonists disclosed herein reduce bile acid content. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to prevent BAM. In some examples, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce BAM symptoms in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, At least 30%, at least 40%, at least 50% or more. In some cases, BAM is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Graft-versus-host disease (GvHD)
移植物抗宿主疾病(GvHD)為於移植來自組織不相容供體(即，遺傳或免疫不同供體)之組織或細胞後產生之醫療併發症。捐贈組織或細胞(移植物)中之免疫細胞識別接受者(宿主)為外來及啟動免疫攻擊。產生GvHD之移植組織或細胞之非限制性實例為血液產品、幹細胞(諸如骨髓細胞)及器官。取決於症狀顯示或發展之位置，存在不同類型之GvHD；例如，皮膚GvHD、肝GvHD、眼GvHD、神經肌肉GvHD、泌尿生殖道GvHD及胃腸(GI)道GvHD。GI道GvHD之症狀包括吞嚥困難、吞嚥疼痛、體重損失、噁心、嘔吐、腹瀉及/或腹部絞痛。GI道GvHD導致黏膜脫落及嚴重腸發炎。膽管上皮細胞發炎對藉由細胞核受體，諸如糖皮質激素受體(GR)、FXR或過氧物酶體增殖物活化之受體(PPAR)控制係順從的。 Graft-versus-host disease (GvHD) is a medical complication following transplantation of tissue or cells from a histo-incompatible donor (ie, a genetically or immunologically different donor). Immune cells in the donated tissue or cells (graft) recognize the recipient (host) as foreign and initiate an immune attack. Non-limiting examples of transplanted tissues or cells that produce GvHD are blood products, stem cells (such as bone marrow cells), and organs. Different types of GvHD exist depending on where symptoms manifest or develop; eg, cutaneous GvHD, hepatic GvHD, ocular GvHD, neuromuscular GvHD, genitourinary GvHD, and gastrointestinal (GI) tract GvHD. Symptoms of GvHD in the GI tract include dysphagia, painful swallowing, weight loss, nausea, vomiting, diarrhea and/or abdominal cramps. GvHD in the GI tract leads to mucosal shedding and severe intestinal inflammation. Biliary epithelial cell inflammation is amenable to control by nuclear receptors such as glucocorticoid receptor (GR), FXR or peroxisome proliferator-activated receptor (PPAR).
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之GvHD或GvHD之併發症。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之GI道GvHD或GI道GvHD之併發症。於一些實例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少哺乳動物之GI道GvHD或GI道GvHD之併發症至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，GI道GvHD或GI道GvHD之併發症減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少由GI道GvHD引起之腸發炎。於一些實施例中，本文中所揭示之FXR促效劑減少由GI道GvHD引起之腸發炎約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。 發炎性腸病 (IBD) 發炎性腸病(IBD)為特徵在於影響結腸及小腸之發炎性病狀之組之自體免疫性疾病。潰瘍性結腸炎(UC)及克羅恩氏病為發炎性腸病之主要類型。FXR活化於患有IBD之患者中減少。經由單獨或與本文中所揭示之附加治療劑組合投與本文中所揭示之FXR促效劑來增加FXR活性可預防及/或減少IBD之症狀。經由單獨或與本文中所揭示之附加治療劑組合投與本文中所揭示之FXR促效劑來增加FXR活性可減少IBD患者之腸發炎。於一些實施例中，FXR活化抑制發炎及保留發炎性腸病中之腸屏障。In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat GvHD or a complication of GvHD in a mammal. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat GI tract GvHD or a complication of GI tract GvHD in a mammal. In some examples, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce GI tract GvHD or complications of GI tract GvHD by at least 5%, at least 10%, At least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some instances, GI tract GvHD or complications of GI tract GvHD are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce intestinal inflammation caused by GvHD in the GI tract. In some embodiments, the FXR agonists disclosed herein reduce intestinal inflammation caused by GvHD in the GI tract by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. Inflammatory Bowel Disease (IBD) Inflammatory bowel disease (IBD) is an autoimmune disease characterized by a group of inflammatory conditions affecting the colon and small intestine. Ulcerative colitis (UC) and Crohn's disease are the main types of inflammatory bowel disease. FXR activation is reduced in patients with IBD. Increasing FXR activity by administering the FXR agonists disclosed herein, alone or in combination with additional therapeutic agents disclosed herein, can prevent and/or reduce symptoms of IBD. Increasing FXR activity by administering the FXR agonists disclosed herein, alone or in combination with additional therapeutic agents disclosed herein, can reduce intestinal inflammation in IBD patients. In some embodiments, FXR activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease.
於胃腸道中表現，已顯示FXR調節上皮細胞之間之緊密連接，其於維持腸道微生物組及黏膜之屏障中係關鍵的。於一些實施例中，FXR亦影響抗菌分子，該等分子藉由胃腸上皮細胞釋放以幫助調節腸道微生物組群。FXR之活化亦減少胃腸道中之膽汁酸產生及繼而減少膽汁酸之量。已知膽汁酸係促發炎性，可使腹瀉症狀惡化，及可影響腸道微生物組。於FXR敲除小鼠中之公開研究證明當暴露於化學刺激物，諸如TNBS (三硝基苯磺酸)中時結腸炎惡化。Expressed in the gastrointestinal tract, FXR has been shown to regulate tight junctions between epithelial cells, which are critical in maintaining the gut microbiome and the mucosal barrier. In some embodiments, FXR also affects antimicrobial molecules that are released by gastrointestinal epithelial cells to help regulate the gut microbiome. Activation of FXR also reduces bile acid production in the gastrointestinal tract and in turn reduces the amount of bile acids. Bile acids are known to be pro-inflammatory, exacerbate diarrhea symptoms, and affect the gut microbiome. Published studies in FXR knockout mice demonstrate that colitis worsens when exposed to chemical stimuli, such as TNBS (trinitrobenzenesulfonic acid).
公開研究亦顯示FXR活化可預防化學誘導之腸發炎，改善結腸炎症狀，抑制上皮滲透性及減少杯狀細胞損失。此外，FXR活化會抑制促發炎性細胞激素於小鼠結腸黏膜中活體內及於不同免疫細胞群體中離體產生。(RM Gadaleta等人，Gut . 2011年4月；60(4):463-72)。Published studies have also shown that FXR activation prevents chemically induced intestinal inflammation, improves colitis symptoms, inhibits epithelial permeability and reduces goblet cell loss. Furthermore, FXR activation inhibited the production of pro-inflammatory cytokines in vivo in mouse colonic mucosa and ex vivo in different immune cell populations. (RM Gadaleta et al. Gut . 2011 Apr;60(4):463-72).
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之IBD。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少腸發炎。於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以預防IBD。於一些實例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少哺乳動物之IBD症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，IBD減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat IBD in a mammal. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce intestinal inflammation. In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to prevent IBD. In some examples, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce IBD symptoms in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, At least 30%, at least 40%, at least 50% or more. In some instances, the IBD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括增加血清FGF-19含量、減少血清C4含量、UC之一或多種臨床症狀之改善或其組合。In some embodiments, treating UC with
於一些實施例中，血清FGF-19含量自基線增加至少10%、至少20%、至少30%、至少40%、至少50%或更多。In some embodiments, serum FGF-19 levels are increased from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
於一些實施例中，血清C4含量自基線減少至少10%、至少20%、至少30%、至少40%、至少50%或更多。In some embodiments, serum C4 levels are reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
UC涉及直腸及其可以連續模式近側延伸以影響結腸之部分或整個結腸。活動性疾病之臨床顯示包括血性腹瀉(具有或不具有黏液)、緊迫感、下墜、腹痛、體重損失、發燒及不適。於患有廣泛或嚴重發炎之患者中，可導致穿孔之急性併發症(諸如嚴重出血及毒性巨結腸)可發生。與一般群體相比，於UC患者中存在結腸直腸癌之增加之風險。UC involves the rectum and can extend proximally in a continuous pattern to affect part or the entire colon. Clinical manifestations of active disease include bloody diarrhea (with or without mucus), urgency, falling, abdominal pain, weight loss, fever, and malaise. In patients with extensive or severe inflammation, acute complications that can lead to perforation, such as severe bleeding and toxic megacolon, can occur. There is an increased risk of colorectal cancer in UC patients compared to the general population.
活動性疾病爆發之短期治療目標為藉由減少活動性疾病之徵兆及症狀之嚴重度且達成其解決來提供患者之減輕。於達成此後，長期目標為減少隨後疾病爆發之頻率。於兩個治療階段(活動性疾病爆發之治療及長期治療)中，相關治療目標為影響疾病過程自身(藉由減少結腸之黏膜發炎)。The short-term treatment goal of active disease outbreaks is to provide patient relief by reducing the severity of signs and symptoms of active disease and achieving their resolution. Once achieved, the long-term goal is to reduce the frequency of subsequent disease outbreaks. In both treatment phases (treatment of active disease outbreaks and long-term treatment), the relevant treatment goal is to influence the disease process itself (by reducing inflammation of the mucosa of the colon).
一或多種臨床症狀之改善係與對照相比。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之個體。於一些實施例中，對照為不接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之全劑量之個體。於一些實施例中，對照為針對在接受FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之前之個體之基線。Improvement in one or more clinical symptoms is compared to a control. In some embodiments, the controls are subjects that do not receive an FXR agonist (eg,
於一些實施例中，一或多種臨床症狀之改善於每日投與化合物1或其醫藥上可接受之鹽約2週、約4週、約6週、約8週、約10週、約12週、約14週、約16週、約18週、約20週、約24週、約26週、約52週、或超過約52週後獲得。In some embodiments, the improvement of one or more clinical symptoms is about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks of daily administration of
UC之一或多種臨床症狀之改善包括直腸出血減少、糞便頻率減少、糞便形式改善、結腸黏膜之內視鏡評價改善、腹痛減少、氣脹減少或其組合。於一些實施例中，UC之一或多種臨床症狀之改善係利用評分指數評估。評分指數包括(但不限於) UC-100評分、潰瘍性結腸炎內視鏡嚴重度指數(UCEIS)、Robarts組織學指數(RHI)、Mayo評分(MS)、發炎性腸病調查表(IBDQ)。Improvement in one or more clinical symptoms of UC includes reduction in rectal bleeding, reduction in stool frequency, improvement in stool pattern, improvement in endoscopic evaluation of colonic mucosa, reduction in abdominal pain, reduction in bloating, or a combination thereof. In some embodiments, improvement in one or more clinical symptoms of UC is assessed using a scoring index. Scoring indices include (but are not limited to) UC-100 score, Ulcerative Colitis Endoscopic Severity Index (UCEIS), Robarts Histology Index (RHI), Mayo Score (MS), Inflammatory Bowel Disease Questionnaire (IBDQ) .
於一些實施例中，複合UC-100評分係用於評估潰瘍性結腸炎之嚴重度。複合UC-100評分係利用下列公式獲得：1 + 16 × Mayo臨床糞便頻率分項分數[0至3] + 6 × Mayo臨床內視鏡分項分數[0至3] + 1 × Robarts組織病理學指數分數[0至33])，其範圍自1 (無疾病活動)至100 (嚴重疾病活動)。In some embodiments, a composite UC-100 score is used to assess the severity of ulcerative colitis. The composite UC-100 score was obtained using the following formula: 1 + 16 × Mayo Clinical Stool Frequency Subscore[0 to 3] + 6 × Mayo Clinical Endoscopy Subscore[0 to 3] + 1 × Robarts Histopathology Index score [0 to 33]) ranging from 1 (no disease activity) to 100 (severe disease activity).
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括UC-100評分自基線至少1個點、至少2個點、至少3個點、至少4個點、至少5個點、至少6個點、至少7個點、至少8個點、至少9個點、至少10個點、至少11個點、至少12個點、至少13個點、至少14個點、至少15個點、至少16個點、至少17個點、至少18個點、至少19個點、至少20個點、至少21個點、至少22個點、至少23個點、至少24個點、至少25個點、至少26個點、至少27個點、至少28個點、至少29個點、至少30個點、至少31個點、至少32個點、至少33個點、至少34個點、至少35個點、至少36個點、至少37個點、至少38個點、至少39個點、至少40個點、至少41個點、至少42個點、至少43個點、至少44個點、至少45個點、至少46個點、至少47個點、至少48個點、至少49個點、至少50個點、或超過50個點之平均變化。In some embodiments, treatment of UC with Compound 1 or a pharmaceutically acceptable salt thereof comprises a UC-100 score of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points from baseline , at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points , at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points , at least 26 points, at least 27 points, at least 28 points, at least 29 points, at least 30 points, at least 31 points, at least 32 points, at least 33 points, at least 34 points, at least 35 points , at least 36 points, at least 37 points, at least 38 points, at least 39 points, at least 40 points, at least 41 points, at least 42 points, at least 43 points, at least 44 points, at least 45 points , at least 46 points, at least 47 points, at least 48 points, at least 49 points, at least 50 points, or the average change over 50 points.
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括總Mayo評分自基線至少1個點、至少2個點、至少3個點、至少4個點、至少5個點、至少6個點、至少7個點、至少8個點、至少9個點、至少10個點、或至少11個點之平均變化。In some embodiments, treatment of UC with
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括部分Mayo評分自基線至少1個點、至少2個點、至少3個點、至少4個點、至少5個點、至少6個點、至少7個點、或至少8個點之平均變化。In some embodiments, treating UC with
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括增加達成臨床反應之個體之比例。於一些實施例中，達成臨床反應之個體之比例增加至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%或超過40%。In some embodiments, treating UC with
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括增加達成臨床緩解之個體之比例。於一些實施例中，達成臨床反應緩解之個體之比例增加至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%或超過40%。In some embodiments, treating UC with
於一些實施例中，利用化合物1或其醫藥上可接受之鹽治療UC包括增加達成無皮質類固醇緩解之個體之比例。無皮質類固醇緩解通常經定義為在特定時間點於基線正在使用之皮質類固醇之患者中之臨床緩解無伴隨皮質類固醇。In some embodiments, treating UC with
於一些實施例中，糞便頻率減少包括少1次糞便/天、少2次糞便/天、少3次糞便/天、少4次糞便/天、少5次糞便/天、少6次糞便/天、或少超過6次糞便/天。In some embodiments, the reduction in stool frequency includes 1 less stool/day, 2 fewer stools/day, 3 fewer stools/day, 4 fewer stools/day, 5 fewer stools/day, 6 fewer stools/day day, or less than 6 stools/day.
於一些實施例中，臨床症狀改善係以按照Bristol糞便量表之糞便類型自基線之變化量測。Bristol糞便量表為經設計以在根據漸增稀薄度在1至7之量表上將糞便分類的醫療輔助。In some embodiments, improvement in clinical symptoms is measured as a change from baseline in stool type according to the Bristol stool scale. The Bristol stool scale is a medical aid designed to classify stool on a scale of 1 to 7 according to increasing thinning.
於一個態樣中，本文中描述一種治療或預防哺乳動物之胃腸疾病或病狀之方法，其包括向該哺乳動物投與本文中所揭示之FXR促效劑。於一些實施例中，該胃腸疾病或病狀為壞死性小腸結腸炎、胃炎、潰瘍性結腸炎、克羅恩氏病、發炎性腸病、大腸激躁症候群、胃腸炎、輻射誘導之腸炎、假膜性結腸炎、化療誘導之腸炎、胃-食管逆流疾病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸乳糜瀉、手術後發炎、胃癌發生、移植物抗宿主疾病或其任何組合。於一些實施例中，該胃腸疾病或病狀為發炎性腸病。 胃腸癌 In one aspect, described herein is a method of treating or preventing a gastrointestinal disease or condition in a mammal comprising administering to the mammal an FXR agonist disclosed herein. In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, Pseudomembranous colitis, chemotherapy-induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, celiac disease, postoperative inflammation, gastric carcinogenesis, graft resistance host disease or any combination thereof. In some embodiments, the gastrointestinal disease or condition is inflammatory bowel disease. Gastrointestinal cancer
FXR主要於暴露於高含量膽酸之組織(諸如完整胃腸道、肝、膽管及膽囊)中表現。最近觀察注意到高脂飲食係與結腸癌發病率正相關。消耗高脂飲食與結腸腔中之膽汁酸之升高之含量(作為膽汁酸之增加之糞便***的結果)相關。消耗西方飲食之個體顯示糞便次級膽汁酸之升高之含量，正如診斷患有結腸癌之患者。升高之次級膽汁酸濃度對結腸上皮架構具有有害作用及通過多重機制，諸如DNA氧化損傷、發炎、NF-κB活化及增強之細胞增殖起作用。結果，可認為膽汁酸為為結腸直腸癌發展之腫瘤促進因子。FXR is primarily manifested in tissues exposed to high levels of bile acids, such as the intact gastrointestinal tract, liver, bile ducts and gallbladder. Recent observations have noted a positive association between a high-fat diet and the incidence of colon cancer. Consumption of a high-fat diet is associated with elevated levels of bile acids in the colonic lumen as a result of increased fecal excretion of bile acids. Individuals consuming a Western diet show elevated levels of fecal secondary bile acids, as do patients diagnosed with colon cancer. Elevated secondary bile acid concentrations have deleterious effects on the colonic epithelial architecture and act through multiple mechanisms such as DNA oxidative damage, inflammation, NF-κB activation and enhanced cell proliferation. As a result, bile acids can be considered as tumor promoting factors for the development of colorectal cancer.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於治療胃腸癌。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與附加治療劑組合用於治療胃腸癌。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)通過活化FXR來減慢或預防胃腸癌之進展。In some embodiments, an FXR agonist (eg,
於一些實施例中，該胃腸癌為肛門癌、結腸癌、食道癌、膽囊癌、膽道癌(biliary tract cancer)、肝癌、膽管癌(cholangiocarcinoma)、胰癌、腹膜癌、直腸癌、結腸直腸癌、小腸癌(small intestine cancer)、胃癌、胃腸間質瘤(GIST)、神經內分泌腫瘤(NET)或小腸癌(small bowel cancer)。於一些實施例中，該胃腸癌為結腸直腸癌。 腎病 In some embodiments, the gastrointestinal cancer is anal cancer, colon cancer, esophageal cancer, gallbladder cancer, biliary tract cancer, liver cancer, cholangiocarcinoma, pancreatic cancer, peritoneal cancer, rectal cancer, colorectal cancer carcinoma, small intestine cancer, gastric cancer, gastrointestinal stromal tumor (GIST), neuroendocrine tumor (NET) or small bowel cancer. In some embodiments, the gastrointestinal cancer is colorectal cancer. kidney disease
於某些實施例中，本文中揭示治療有需要個體之腎病之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑及附加治療劑。於一些實施例中，該腎病與肝病相關聯。於一些實施例中，該腎病與纖維化肝病相關聯。於一些實施例中，該腎病與代謝性肝病相關聯。於一些實施例中，該腎病與代謝性病狀，諸如(但不限於)糖尿病、代謝症候群、NAFLD、胰島素抗性、脂肪酸代謝病症及膽汁鬱積相關聯。於一些實施例中，該腎病為糖尿病性腎病、與纖維化相關聯之腎病、與纖維化不相關聯之腎病、腎纖維化或其任何組合。於一些實施例中，該腎病與小管間質性腎炎/腎病變相關聯。於一些實施例中，該腎病與腎小球性腎炎/腎病變相關聯。In certain embodiments, disclosed herein are methods of treating renal disease in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist and an additional therapeutic agent. In some embodiments, the kidney disease is associated with liver disease. In some embodiments, the kidney disease is associated with fibrotic liver disease. In some embodiments, the kidney disease is associated with metabolic liver disease. In some embodiments, the renal disease is associated with metabolic conditions such as, but not limited to, diabetes, metabolic syndrome, NAFLD, insulin resistance, disorders of fatty acid metabolism, and cholestasis. In some embodiments, the nephropathy is diabetic nephropathy, nephropathy associated with fibrosis, nephropathy not associated with fibrosis, renal fibrosis, or any combination thereof. In some embodiments, the renal disease is associated with tubulointerstitial nephritis/nephropathy. In some embodiments, the renal disease is associated with glomerulonephritis/nephropathy.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於治療小管間質性腎炎/腎病變及/或腎小球性腎炎/腎病變。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於治療小管間質性腎炎/腎病變。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於治療腎小球性腎炎/腎病變。In some embodiments, an FXR agonist (eg,
於一些實施例中，該小管間質性腎炎/腎病變為藥物誘導之小管間質性腎炎/腎病變、毒素誘導之小管間質性腎炎、輻射誘導之小管間質性腎炎、缺血誘導之小管間質性腎炎或特發性小管間質性腎炎。In some embodiments, the tubulointerstitial nephritis/nephropathy is drug-induced tubulointerstitial nephritis/nephropathy, toxin-induced tubulointerstitial nephritis, radiation-induced tubulointerstitial nephritis, ischemia-induced tubulointerstitial nephritis or idiopathic tubulointerstitial nephritis.
於一些實施例中，該腎小球性腎炎/腎病變為IgA腎病、局部區段性腎小球硬化、最小變化腎小球性腎炎、藥物誘導之腎小球性腎炎、感染誘導(鏈球菌後)之腎小球性腎炎、血管炎誘導之腎小球性腎炎、或繼發於全身性疾病(包括(但不限於)澱粉樣變性及全身性紅斑狼瘡)之腎小球性腎炎。糖尿病性腎病 In some embodiments, the glomerulonephritis/nephropathy is IgA nephropathy, focal segmental glomerulosclerosis, minimal change glomerulonephritis, drug-induced glomerulonephritis, infection-induced (Streptococcus) glomerulonephritis, vasculitis-induced glomerulonephritis, or glomerulonephritis secondary to systemic diseases including, but not limited to, amyloidosis and systemic lupus erythematosus. diabetic nephropathy
於一些實施例中，促進腎病之因素包括高脂血、高血壓、高血糖及蛋白尿，其所有導致對腎之進一步損傷及進一步刺激細胞外基質沉積。此外，葡萄糖之調節異常導致刺激細胞激素釋放及上調細胞外基質沉積。不管主要原因，對腎之損害可導致腎纖維化及伴隨腎功能喪失。In some embodiments, factors that promote kidney disease include hyperlipidemia, hypertension, hyperglycemia, and proteinuria, all of which lead to further damage to the kidney and further stimulation of extracellular matrix deposition. In addition, dysregulation of glucose results in stimulation of cytokine release and upregulation of extracellular matrix deposition. Regardless of the primary cause, damage to the kidneys can lead to renal fibrosis and concomitant loss of renal function.
糖尿病性腎病為特徵在於腎之小球損傷之腎病。糖尿病促進反應性氧物質之過度產生，其導致腎病症候群及腎小球結疤。隨著糖尿病性腎病進展，腎小球過濾屏障(GFB)越來越被損壞及因此，血液中之蛋白質洩漏通過該屏障及於鮑曼氏(Bowman’s)空間中累積。Diabetic nephropathy is a nephropathy characterized by damage to the glomeruli of the kidneys. Diabetes promotes the overproduction of reactive oxygen species, which leads to nephrotic syndrome and glomerular scarring. As diabetic nephropathy progresses, the glomerular filtration barrier (GFB) is increasingly damaged and, as a result, proteins in the blood leak through this barrier and accumulate in Bowman's space.
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之糖尿病性腎病。於一些實例中，FXR促效劑及附加治療劑減少哺乳動物之糖尿病性腎病症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，糖尿病性腎病減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。腎纖維化 In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat diabetic nephropathy in a mammal. In some examples, the FXR agonist and the additional therapeutic agent reduce diabetic nephropathy symptoms in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more many. In some instances, the diabetic nephropathy is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent. renal fibrosis
腎纖維化之特徵在於纖維母細胞之活化及細胞外基質或結蹄組織於腎中之過量沉積，其為慢性腎病之標誌。FXR於保護免於腎纖維化中起著重要作用。FXR之活化抑制腎纖維化及減少細胞外基質蛋白於腎中之累積。Renal fibrosis is characterized by activation of fibroblasts and excessive deposition of extracellular matrix or hoof tissue in the kidney, which are hallmarks of chronic kidney disease. FXR plays an important role in protection from renal fibrosis. Activation of FXR inhibits renal fibrosis and reduces the accumulation of extracellular matrix proteins in the kidney.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於治療與腎纖維化相關聯之疾病或病狀。腎纖維化可自各種疾病及對腎之損害產生。此等疾病及損害之實例包括慢性腎病、代謝症候群、膀胱輸尿管逆流、小管間質性腎纖維化、IgA腎病、糖尿病(包括糖尿病性腎病)、奧爾波氏(Alport)症候群、HIV相關聯之腎病、結果腎小球性腎炎(GN) (包括但不限於局部區段性腎小球硬化及膜性腎小球腎炎)、腎小球膜毛細血管GN及結果間質纖維化及腎小管萎縮(IFTA)，包括(但不限於)急性腎損傷(AKI)後之恢復、急性阻塞性腎病及藥物誘導之腎纖維化。In some embodiments, an FXR agonist (eg,
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之腎纖維化。於一些實例中，FXR促效劑及附加治療劑減少哺乳動物之腎纖維化症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，腎纖維化減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat renal fibrosis in a mammal. In some examples, FXR agonists and additional therapeutic agents reduce symptoms of renal fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more many. In some instances, renal fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一個態樣中，本文中描述一種治療或預防哺乳動物之腎疾病或病狀之方法，其包括向該哺乳動物投與本文中所揭示之FXR促效劑。於一些實施例中，該腎疾病或病狀為糖尿病性腎病、與纖維化相關聯之腎病、與纖維化不相關聯之腎病、腎纖維化、與代謝性疾病相關聯之腎病、慢性腎病、多囊性腎病、急性腎病或其任何組合。 發炎 In one aspect, described herein is a method of treating or preventing a kidney disease or condition in a mammal comprising administering to the mammal an FXR agonist disclosed herein. In some embodiments, the kidney disease or condition is diabetic nephropathy, nephropathy associated with fibrosis, nephropathy not associated with fibrosis, renal fibrosis, nephropathy associated with metabolic disease, chronic kidney disease, Polycystic kidney disease, acute kidney disease, or any combination thereof. fever
於某些實施例中，本文中揭示治療或預防有需要個體之發炎之方法，其包括向該個體投與法尼醇X受體(FXR)促效劑及附加治療劑。於一些實施例中，該附加治療劑為抗纖維化治療劑、抗發炎劑、代謝治療劑、抗發炎劑或本文中所述之其他治療劑中之任一者。In certain embodiments, disclosed herein are methods of treating or preventing inflammation in an individual in need thereof, comprising administering to the individual a farnesoid X receptor (FXR) agonist and an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anti-fibrotic therapeutic agent, an anti-inflammatory agent, a metabolic therapeutic agent, an anti-inflammatory agent, or any of the other therapeutic agents described herein.
於一些實施例中，該發炎為肝發炎。於一些實施例中，該肝發炎為急性肝炎、慢性肝炎、或猛爆性肝炎。於一些實施例中，該肝發炎為病毒性肝炎、細菌性肝炎、寄生蟲性肝炎、毒物及藥物誘導之肝炎、酒精性肝炎、自體免疫性肝炎、非酒精性脂肪性肝炎(NASH)、新生兒肝炎或缺血性肝炎。於一些實施例中，該病毒性肝炎為A型肝炎、B型肝炎、C型肝炎、D型肝炎或E型肝炎。於一些實施例中，該肝發炎伴隨纖維化肝病或代謝性肝病。In some embodiments, the inflammation is liver inflammation. In some embodiments, the liver inflammation is acute hepatitis, chronic hepatitis, or fulminant hepatitis. In some embodiments, the liver inflammation is viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), Neonatal hepatitis or ischemic hepatitis. In some embodiments, the viral hepatitis is hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. In some embodiments, the liver inflammation is accompanied by fibrotic liver disease or metabolic liver disease.
於一些實施例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合用於治療哺乳動物之發炎或發炎性病狀。於一些實例中，本文中所揭示之FXR促效劑與如本文中所揭示之另一治療劑組合使用以減少哺乳動物之發炎或發炎性病狀之症狀至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。於一些情況下，發炎或發炎性病狀減少約5%至約50%、約5%至約25%、約10%至約20%、或約10%至約30%。於一些實施例中，該附加治療劑為抗發炎劑、代謝劑或抗纖維化劑。In some embodiments, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to treat inflammation or an inflammatory condition in a mammal. In some examples, an FXR agonist disclosed herein is used in combination with another therapeutic agent as disclosed herein to reduce the symptoms of inflammation or an inflammatory condition in a mammal by at least 5%, at least 10%, at least 15% , at least 20%, at least 30%, at least 40%, at least 50% or more. In some instances, the inflammation or inflammatory condition is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolizing agent, or an anti-fibrotic agent.
於一個態樣中，本文中描述一種治療或預防哺乳動物之發炎性病狀之方法，其包括向該哺乳動物投與本文中所揭示之FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，該發炎性病狀包括肝發炎、腎發炎、胃腸發炎或其任何組合。FXR 促效劑 In one aspect, described herein is a method of treating or preventing an inflammatory condition in a mammal comprising administering to the mammal an FXR agonist disclosed herein (eg,
於一些實施例中，用於所揭示方法中以治療或預防肝病、胃腸疾病、代謝性肝病或纖維化肝病之FXR促效劑為本文中所述化合物。於一個態樣中，本文中所述化合物包含其醫藥上可接受之鹽、前藥、活性代謝物及醫藥上可接受之溶劑化物。於一些實施例中，該FXR促效劑為非膽汁酸、膽汁酸類似物或其他天然FXR配位體。In some embodiments, the FXR agonist used in the disclosed methods to treat or prevent liver disease, gastrointestinal disease, metabolic liver disease, or fibrotic liver disease is a compound described herein. In one aspect, the compounds described herein include pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof. In some embodiments, the FXR agonist is a non-bile acid, bile acid analog, or other natural FXR ligand.
於一個態樣中，用於本文中所述方法中之任一者中之FXR促效劑具有非膽汁酸化學結構。於一些實施例中，當向哺乳動物投與時，用於本文中所述方法中之任一者中之FXR促效劑具有持續暴露。於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑具有與FXR之連續標靶接合。於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑適用於每日一次口服給藥。於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑具有非膽汁酸化學結構，持續暴露與連續標靶接合，且適用於每日一次口服給藥。In one aspect, the FXR agonist used in any of the methods described herein has a non-bile acid chemical structure. In some embodiments, the FXR agonist used in any of the methods described herein has sustained exposure when administered to a mammal. In some embodiments, the FXR agonist used in any of the methods described herein has continuous target engagement to FXR. In some embodiments, the FXR agonist used in any of the methods described herein is suitable for once-daily oral administration. In some embodiments, the FXR agonist used in any of the methods described herein has a non-bile acid chemical structure, is continuously exposed to continuous target engagement, and is suitable for once-daily oral administration.
於一些實施例中，用於本文中所述實施例中之任一者中之FXR促效劑為述於以下之化合物：2015年3月13日申請之國際申請案第PCT/US2015/020582號；2016年9月12日申請之申請案第15/263,048號；2015年3月13日申請之國際申請案第PCT/US2015/020552號；2016年9月12日申請之申請案第15/263,033號；2016年9月16日申請之國際申請案第PCT/US2016/052268號；2016年9月16日申請之國際申請案第PCT/US2016/052274號；2016年9月16日申請之國際申請案第PCT/US2016/052275號；2016年9月16日申請之國際申請案第PCT/US2016/052270號；2018年3月14日申請之國際申請案第PCT/US2018/022488號；2018年3月14日申請之國際申請案第PCT/US2018/022489號；2018年3月14日申請之國際申請案第PCT/US2018/022497號；2018年3月14日申請之國際申請案第PCT/US2018/022513號。In some embodiments, the FXR agonist used in any of the embodiments described herein is a compound described in: International Application No. PCT/US2015/020582, filed March 13, 2015 ; Application No. 15/263,048, filed on September 12, 2016; International Application No. PCT/US2015/020552, filed on March 13, 2015; Application No. 15/263,033, filed on September 12, 2016 No.; International Application No. PCT/US2016/052268 filed on September 16, 2016; International Application No. PCT/US2016/052274 filed on September 16, 2016; International Application filed on September 16, 2016 Case No. PCT/US2016/052275; International Application No. PCT/US2016/052270 filed on September 16, 2016; International Application No. PCT/US2018/022488 filed on March 14, 2018; March 2018 International Application No. PCT/US2018/022489 filed on March 14; International Application No. PCT/US2018/022497 filed on March 14, 2018; International Application No. PCT/US2018 filed on March 14, 2018 /022513.
於一些實施例中，用於本文中所述實施例中之任一者中之FXR促效劑為具有下列化合物1結構之化合物：
化合物1亦稱作「反式
-N
-(3-(1-環丙基-1H
-吡唑-4-基)苯基)-4-羥基-N
-((反式
-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺」。其他名字可係已知。
奧貝膽酸(OCA)為含有膽汁酸化學結構之FXR促效劑。於公開之臨床研究中，OCA已證明作為FXR促效劑之臨床功效，但是與在較高投與劑量下之不利副作用(諸如搔癢、增加之LDL膽固醇及肝毒性)相關聯。於一些實施例中，於評估FXR促效劑結合至FXR之適宜活體外檢定中，化合物1證明較OCA至少7倍更強效。於一些實施例中，化合物1之增加之效能指示相對於OCA之更寬潛在治療窗。Obeticholic acid (OCA) is an FXR agonist containing the chemical structure of bile acids. In published clinical studies, OCA has demonstrated clinical efficacy as an FXR agonist, but is associated with adverse side effects such as itching, increased LDL cholesterol, and hepatotoxicity at higher administered doses. In some embodiments,
於一些實施例中，化合物1於臨床前動物模型中基於藥物動力學及藥效動力學標誌物顯示持續FXR接合。於一些實施例中，化合物1證明持續FXR接合，其允許化合物1之每日一次給藥。In some embodiments,
於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑具有非膽汁酸化學結構。於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑具有膽汁酸化學結構。In some embodiments, the FXR agonist used in any of the methods described herein has a non-bile acid chemical structure. In some embodiments, the FXR agonist used in any of the methods described herein has a bile acid chemical structure.
於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑為化合物1或其醫藥上可接受之鹽；奧貝膽酸或其醫藥上可接受之鹽(Intercept)；西洛弗索(cilofexor)或其醫藥上可接受之鹽(Gilead)；EDP-305或其醫藥上可接受之鹽(Enanta)；曲匹弗索(tropifexor)或其醫藥上可接受之鹽(Novartis)；EYP001或其醫藥上可接受之鹽(Enyo)；LMB673或其醫藥上可接受之鹽(Novartis)；TERN-101或其醫藥上可接受之鹽(Terns)；AGN-242266或其醫藥上可接受之鹽(Allergan)。於一些實施例中，用於本文中所述方法中之任一者中之FXR促效劑為西洛弗索或其醫藥上可接受之鹽；EDP-305或其醫藥上可接受之鹽；曲匹弗索或其醫藥上可接受之鹽；EYP001或其醫藥上可接受之鹽；LMB673或其醫藥上可接受之鹽；TERN-101或其醫藥上可接受之鹽；AGN-242266或其醫藥上可接受之鹽。於一些實施例中，該FXR促效劑為非沙明(fexaramine)或其醫藥上可接受之鹽。某些術語 In some embodiments, the FXR agonist used in any of the methods described herein is
本文中所用之節標題僅出於組織目的且不應解釋為限制所述標的。Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.
除非另有指定，否則本申請案中所用之下列術語具有以下給定之定義。術語「包含(including)」以及其他形式，諸如「包含(include/includes/included」之使用非限制性。Unless otherwise specified, the following terms used in this application have the definitions given below. The use of the term "including" and other forms such as "include/includes/included" is non-limiting.
如本文中所用，關於調配物、組合物或成分之術語「可接受」意指對正在治療之哺乳動物之一般健康不具有持續有害影響。As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means not having a persistent deleterious effect on the general health of the mammal being treated.
如本文中所用，術語「調節」意指與標靶直接或間接相互作用以便改變標靶之活性，包括(僅舉例而言)增強標靶之活性、抑制標靶之活性、限制標靶之活性或延伸標靶之活性。As used herein, the term "modulate" means interact directly or indirectly with a target in order to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target or extend the activity of the target.
如本文中所用，術語「調節劑」係指與標靶直接或間接相互作用之分子。相互作用包括(但不限於)促效劑、部分促效劑、反向促效劑、拮抗劑、降解劑或其組合之相互作用。於一些實施例中，調節劑為促效劑。As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.
如本文中所用，術語「投與(administer/administering/administration)」及類似者係指用於使化合物或組合物能遞送至生物作用之所需位點之方法。此等方法包括(但不限於)口服途徑、十二指腸內途徑、非經腸注射(包括靜脈內、皮下、腹膜內、肌肉內、血管內或輸注)、局部及直腸投與。熟習此項技術者熟悉利用本文中所述化合物及方法採用之投與技術。於一些實施例中，本文中所述化合物及組合物經口投與。As used herein, the terms "administer/administering/administration" and the like refer to methods used to enable delivery of a compound or composition to the desired site of biological action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
如本文中所用，術語「共同投與」或類似者意指包含向單個患者投與所選治療劑及意欲包含治療方案，其中藉由相同或不同投與途徑或在相同或不同時間投與藥劑。As used herein, the term "co-administered" or the like is meant to encompass the administration of a selected therapeutic agent to a single patient and is intended to encompass a therapeutic regimen wherein the agents are administered by the same or different routes of administration or at the same or different times .
如本文中所用，術語「有效量」或「治療上有效量」係指正在投與之藥劑或化合物之足夠量，其將在一定程度上減輕正在治療之疾病或病狀之症狀中之一或多者。結果包括減少及/或減輕疾病之徵兆、症狀或原因，或生物系統之任何其他所需改變。例如，用於治療用途之「有效量」為提供疾病症狀之臨床上顯著減少所需之包含如本文中所揭示之化合物之組合物的量。於任何個別情況下之適宜「有效」量視情況使用諸如劑量遞增研究之技術確定。As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the agent or compound being administered that will alleviate to some extent one of the symptoms of the disease or condition being treated or many. Results include reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired changes in biological systems. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined as appropriate using techniques such as dose escalation studies.
如本文中所用，術語「增強(enhance/enhancing)」意指增加或延長所需效應之效能或持續時間。因此，關於增強治療劑之效應，術語「增強」係指在效能或持續時間方面增加或延長其他治療劑對系統之效應之能力。如本文中所用，「增強有效量」係指適當增強所需系統中之另一治療劑之效應的量。As used herein, the term "enhance/enhancing" means to increase or prolong the potency or duration of a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong, in potency or duration, the effect of another therapeutic agent on a system. As used herein, an "enhancing-effective amount" refers to an amount that appropriately enhances the effect of another therapeutic agent in the desired system.
如本文中所用，術語「醫藥組合」意指自將超過一種活性成分混合或組合產生及包含活性成分之固定及非固定組合二者之產品。術語「固定組合」意指活性成分(例如，本文中所述化合物或其醫藥上可接受之鹽)及輔劑均以單一實體或劑量之形式向患者同時投與。術語「非固定組合」意指活性成分(例如，本文中所述化合物或其醫藥上可接受之鹽)及輔劑作為單獨實體同時、合併或依序向患者投與無特定介入時間限制，其中此投與提供兩種化合物於患者體內之有效含量。後者亦適用於混合療法，例如，投與三種或更多種活性成分。As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining more than one active ingredient and comprising both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both the active ingredient (eg, a compound described herein, or a pharmaceutically acceptable salt thereof) and an adjuvant are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients (eg, a compound described herein, or a pharmaceutically acceptable salt thereof) and adjuvants are administered to a patient simultaneously, combined or sequentially as separate entities without a specific intervening time limit, wherein This administration provides effective levels of both compounds in the patient's body. The latter also applies to combination therapy, eg, the administration of three or more active ingredients.
術語「個體」或「患者」包含哺乳動物。哺乳動物之實例包括(但不限於)哺乳動物類別之任何成員：人類、非人類靈長類動物(諸如黑猩猩)及其他類人猿及猴物種。於一個態樣中，該哺乳動物為人類。The term "individual" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates (such as chimpanzees), and other ape and monkey species. In one aspect, the mammal is a human.
如本文中所用，術語「治療(treat/treating/treatment)」包括預防上及/或治療上減輕、減少或改善疾病或病狀之至少一種症狀，預防另外症狀，抑制疾病或病狀，例如，抑制疾病或病狀之發展，減輕疾病或病狀，引起疾病或病狀之消退，停止疾病或病狀之進展，減輕由疾病或病狀引起之狀況，或停止疾病或病狀之症狀。As used herein, the term "treat/treating/treatment" includes prophylactically and/or therapeutically alleviating, reducing or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, eg, Inhibit the development of a disease or condition, alleviate a disease or condition, cause regression of a disease or condition, halt the progression of a disease or condition, alleviate a condition caused by a disease or condition, or stop the symptoms of a disease or condition.
術語「約(about/approximately)」意指於特定值之可接受之誤差範圍內，如由一般技術者所測定，其將部分取決於該值如何量測或測定，例如，量測系統之限制。於本申請案及申請專利範圍中描述特定值之情況下，除非另有指定，否則術語「約」應假設為意指平均值，特定值之可接受誤差範圍。醫藥組合物 The term "about/approximately" means within an acceptable margin of error for a particular value, as determined by one of ordinary skill, which will depend in part on how the value is measured or determined, eg, limitations of the measurement system . Where particular values are described in this application and the claimed scope, unless otherwise specified, the term "about" shall be assumed to mean an average value, an acceptable range of error for the particular value. pharmaceutical composition
醫藥組合物係以習知方式使用一或多種醫藥上可接受之活性成分調配，該等活性成分促進活性化合物加工成醫藥上使用之製劑。適當調配物係取決於所選投與途徑。本文中所述之醫藥組合物之概述見於(例如) Remington: The Science and Practice of Pharmacy，第19版(Easton, Pa.: Mack Publishing Company, 1995)；Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975；Liberman, H.A.及Lachman, L.編輯，Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980；及Pharmaceutical Dosage Forms and Drug Delivery Systems，第7版(Lippincott Williams & Wilkins1999)中，此揭示內容以引用的方式併入本文中。Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable active ingredients that facilitate processing of the active compounds into preparations for pharmaceutical use. Appropriate formulations will depend on the route of administration chosen. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999 ), this disclosure is incorporated herein by reference.
於一些實施例中，本文中所述之醫藥組合物係非經腸或經腸投與。於一些實施例中，本文中所述之醫藥組合物係經口投與。In some embodiments, the pharmaceutical compositions described herein are administered parenterally or enterally. In some embodiments, the pharmaceutical compositions described herein are administered orally.
於一些實施例中，本文中所述之醫藥組合物係呈粉末、錠劑、膠囊、懸浮液、液體、分散液、溶液或乳液之形式。In some embodiments, the pharmaceutical compositions described herein are in the form of powders, tablets, capsules, suspensions, liquids, dispersions, solutions or emulsions.
於一些實施例中，適用於口服投與之醫藥組合物以離散單元，諸如各含有預定量之活性成分之膠囊、丸劑或錠劑；以粉末或顆粒；以含於水性液體或非水性液體中之溶液或懸浮液；或以水包油液體乳液或油包水液體乳液呈現。In some embodiments, pharmaceutical compositions suitable for oral administration are in discrete units, such as capsules, pills, or lozenges, each containing a predetermined amount of the active ingredient; in powders or granules; in aqueous or non-aqueous liquids as a solution or suspension; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
經口使用之醫藥組合物包括錠劑、由明膠製得之推入配合膠囊，以及由明膠及增塑劑(諸如甘油或山梨醇)製得之軟密封膠囊。錠劑藉由壓縮或模製，視情況利用一或多種輔助成分製備。壓縮錠劑係藉由將呈自由流動形式(諸如粉末或顆粒)之視情況與黏合劑、惰性稀釋劑或潤滑劑、表面活性劑或分散劑混合之活性成分於適宜機器中壓縮來製備。模製錠劑係藉由將利用惰性液體稀釋劑弄濕之成粉末之化合物的混合物於適宜機器中模製來製備。於一些實施例中，該等錠劑經包衣或刻痕及經調配以便提供其中活性成分之緩慢或可控釋放。用於口服投與之所有調配物應以適用於此投與之劑量。推入配合膠囊含有活性成分與填料(諸如乳糖)、黏合劑(諸如澱粉)及/或潤滑劑(諸如滑石或硬脂酸鎂)及視情況穩定劑之混合物。於軟膠囊中，活性化合物溶解或懸浮於適宜液體(諸如脂肪油、液體石蠟或液體聚乙二醇)中。於一些實施例中，添加穩定劑。利用適宜塗料提供糖衣丸核。出於此目的，使用濃縮糖溶液，其視情況含有***膠、滑石、聚乙烯吡咯啶酮、卡波姆膠、聚乙二醇及/或二氧化鈦、漆溶液及適宜有機溶劑或溶劑混合物。於一些實施例中，將染料或顏料添加至錠劑或糖衣丸塗料中以識別或表徵活性化合物劑量之不同組合。Pharmaceutical compositions for oral use include lozenges, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets are prepared by compression or molding, as appropriate, with one or more accessory ingredients. Compressed tablets are prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent or lubricant, surface active or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the lozenges are coated or scored and formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions are used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In some embodiments, dyestuffs or pigments are added to the dragee or dragee coatings for identification or to characterize different combinations of active compound doses.
於一些實施例中，醫藥組合物經調配用於藉由注射(例如，團式注射或連續輸注)之非經腸投與。於一些實施例中，用於注射之調配物係以單位劑型(例如，以安瓿或多劑量容器)呈現，具有添加之防腐劑。於一些實施例中，該等組合物採用此等形式，如含於油性或水性媒劑中之懸浮液、溶液或乳液，及含有調配劑，諸如懸浮劑、穩定劑及/或分散劑。於一些實施例中，該等組合物以單位劑量或多劑量容器(例如密封安瓿及小瓶)呈現，及以粉末形式或在僅需要在使用之前立即添加無菌液體載劑(例如，鹽水或無菌無熱原水)之冷凍乾燥(凍乾)條件下儲存。於一些實施例中，臨時注射溶液及懸浮液自先前所述類型之無菌粉末、顆粒及錠劑製備。In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection (eg, bolus injection or continuous infusion). In some embodiments, formulations for injection are presented in unit dosage form (eg, in ampoules or in multi-dose containers) with an added preservative. In some embodiments, the compositions take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In some embodiments, the compositions are presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials), and in powder form or simply requiring the addition of a sterile liquid carrier (e.g., saline or sterile non-dose immediately before use) Pyrogen water) under freeze-dried (lyophilized) conditions. In some embodiments, extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the type previously described.
於一些實施例中，用於非經腸投與之醫藥組合物包括含有抗氧化劑、緩衝劑、抑菌劑及致使調配物與意欲接受者之血液等滲之溶質之活性化合物的水性及非水性(油性)無菌注射溶液；及包含懸浮劑及增稠劑之水性及非水性無菌懸浮液。適宜親脂性溶劑或媒劑包括脂肪油(諸如芝麻油)或合成脂肪酸酯(諸如油酸乙酯或甘油三酯)或脂質體。於一些實施例中，水性注射懸浮液含有增加懸浮液之黏度之物質，諸如羧甲基纖維素鈉、山梨醇或聚葡糖。於一些實施例中，視情況，該懸浮液含有適宜穩定劑或增加化合物之溶解度以允許製備高度濃縮溶液之劑。In some embodiments, pharmaceutical compositions for parenteral administration include aqueous and non-aqueous active compounds containing antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient. (oily) sterile injectable solutions; and aqueous and non-aqueous sterile suspensions containing suspending and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In some embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or polydextrose. In some embodiments, the suspension optionally contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
於一些實施例中，醫藥組合物亦經調配為儲積製劑。於一些實施例中，此等長效調配物藉由移植(例如經皮下或經肌肉內)或藉由肌肉內注射投與。因此，例如，化合物係利用適宜聚合或疏水性材料(例如，呈含於可接受油中之乳液)或離子交換樹脂，或呈微溶衍生物，例如，呈微溶鹽調配。In some embodiments, the pharmaceutical composition is also formulated as a depot. In some embodiments, these long-acting formulations are administered by transplantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds are formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
應瞭解，於一些實施例中，除了以上特別提及之成分外，考慮到所討論之調配物之類型，本文中所述之化合物及組合物包含此項技術中習知之其他劑。例如，於一些實施例中，適用於口服投與之本文中所述之化合物及組合物包含調味劑。給藥方法及治療方案 It will be appreciated that, in some embodiments, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein include other agents known in the art, given the type of formulation in question. For example, in some embodiments, the compounds and compositions described herein suitable for oral administration include flavoring agents. Method of administration and treatment plan
於一個實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於製備用於治療或預防哺乳動物之本文中所述疾病或病狀中之任一者的藥劑。治療需要此治療之哺乳動物之本文中所述疾病或病狀中之任一者的方法涉及以治療上有效量向該哺乳動物投與醫藥組合物，該等醫藥組合物包含FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)、活性代謝物、前藥。In one embodiment, an FXR agonist (eg,
於某些實施例中，投與含有本文中所述之該(等)化合物之組合物用於預防性及/或治療性治療。於某些治療性應用中，以足以治癒或至少部分抑制疾病或病狀之症狀中之至少一者的量向已患有該疾病或病狀之患者投與該等組合物。用於此用途之有效量取決於疾病或病狀之嚴重度及過程、先前療法、患者之健康狀態、體重及對藥物之反應、及治療醫師之判斷。治療上有效量視情況藉由包括(但不限於)劑量遞增及/或劑量範圍臨床試驗之方法測定。In certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one of the symptoms of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous therapy, the patient's state of health, weight and response to the drug, and the judgment of the treating physician. A therapeutically effective amount is determined by methods including, but not limited to, dose escalation and/or dose-ranging clinical trials, as appropriate.
於預防性應用中，向易感或原本具有特定疾病、病症或病狀之風險之患者投與含有FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之組合物。此量經定義為「預防上有效量或劑量」。於此用途中，精確量亦取決於患者之健康狀態、體重及類似者。當用於患者中時，用於此用途之有效量將取決於疾病之嚴重度及過程、病症或病狀、先前療法、患者之健康狀態及對藥物之反應、及治療醫師之判斷。於一個態樣中，預防性治療包括向先前經歷正在治療及目前緩解之疾病之至少一個症狀之哺乳動物投與包含FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之醫藥組合物以預防疾病或病狀之症狀之復發。In prophylactic applications, a composition containing an FXR agonist (eg,
於患者之病狀不改善的某些實施例中，在醫生之裁量後，長期投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)，即，持續延長之時間段，包括整個患者生命之持續時間以改善或以其他方式控制或限制患者之疾病或病狀之症狀。In certain embodiments where the patient's condition does not improve, the FXR agonist (e.g.,
於患者之狀態確實改善的某些實施例中，暫時減少或暫時停止正在投與之藥物之劑量持續某個時間長度(即，「藥物假期」)。於特定實施例中，藥物假期之長度係介於約2天與約1年之間，包括(僅舉例而言)約2天、約3天、約4天、約5天、約6天、約7天、約10天、約12天、約15天、約20天、約28天或超過約28天。藥物假期期間之劑量減少為(僅舉例而言)約10%至100%，包括(僅舉例而言)約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%及約100%。In certain embodiments where the patient's status does improve, the dose of the drug being administered is temporarily reduced or temporarily stopped for a certain length of time (ie, a "drug holiday"). In particular embodiments, the length of the drug holiday is between about 2 days and about 1 year, including, by way of example only, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, About 7 days, about 10 days, about 12 days, about 15 days, about 20 days, about 28 days, or more than about 28 days. Dose reduction during drug holidays is, by way of example only, about 10% to 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% , about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and about 100%.
一旦患者之病狀之改善發生，若必要，則投與維持劑量。隨後，於特定實施例中，減少投與劑量或頻率或二者(作為症狀之函數)至保持改善之疾病、病症或病狀之水平。然而，於某些實施例中，患者在症狀之復發後需要長期間歇治療。Once improvement in the patient's condition occurs, a maintenance dose is administered, if necessary. Subsequently, in certain embodiments, the dose or frequency of administration, or both, is reduced (as a function of symptoms) to a level that maintains the improved disease, disorder or condition. However, in certain embodiments, patients require intermittent treatment on a long-term basis following a recurrence of symptoms.
於一個態樣中，向需要FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之療法之人類每日投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每天一次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每天兩次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每隔一天投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每週兩次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。In one aspect, a human in need of therapy with an FXR agonist (eg,
於一些實例中，每天一次、每天兩次或更多次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實例中，每天兩次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每日、每天、每隔一天、每週5天、每週一次、每隔一週、每月2週、每月3週、每月一次、每月兩次、每月三次或更多次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，每日兩次(例如，早上及晚上)投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)至少1天、2天、3天、4天、5天、6天、1週、2週、3週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月、12個月、18個月、2年、3年、4年、5年、10年、或更長時間。於一些實施例中，每日兩次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)持續至少或約1週、2週、3週、1個月、2個月、3個月、4個月、5個月、6個月或更長時間。於一些實施例中，每日一次、每日兩次、每日三次、每日四次或每日超過四次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)持續至少或約1週、2週、3週、1個月、2個月、3個月、4個月、5個月、6個月或更長時間。In some examples, the FXR agonist (eg,
一般而言，用於治療人類之本文中所述疾病或病狀所採用之FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之劑量通常於約0.01 mg/kg至約10 mg/kg體重/劑量之範圍內。於一個實施例中，所需劑量以單一劑量或以同時(或歷時短時間段)或以適宜間隔投與之分開劑量方便呈現，例如，以每天兩個、三個、四個或更多個分劑量。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)以每天一次同時(或歷時短時間段)投與之分開劑量方便呈現。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)以每天兩次以相等比率投與之分開劑量方便呈現。In general, the dosage of an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)以約0.01 mg/kg至約10 mg/kg體重/劑量之劑量向人類經口投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)以連續給藥時程表向人類投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)以連續每日給藥時程表向人類投與。In some embodiments, the FXR agonist (eg,
術語「連續給藥時程表」係指以規則間隔投與特定治療劑。於一些實施例中，連續給藥時程表係指以規則間隔投與特定治療劑而無來自特定治療劑之任何藥物假期。於一些其他實施例中，連續給藥時程表係指以週期投與特定治療劑。於一些其他實施例中，連續給藥時程表係指以藥物投與之週期接著來自特定治療劑之藥物假期(例如，洗出期或不投與藥物時之其他此時間段)投與特定治療劑。例如，於一些實施例中，每天一次、每天兩次、每天三次、每週一次、每週兩次、每週三次、每週四次、每週五次、每週六次、每週七次、每隔一天、每三天、每四天投與治療劑，每日持續一週，接著一週不投與治療劑，每日持續兩週，接著一或兩週不投與治療劑，每日持續三週，接著一週、兩週或三週不投與治療劑，每日持續四週，接著一週、兩週、三週或四週不投與治療劑，每週投與治療劑，接著一週不投與治療劑，或每兩週投與治療劑，接著兩週不投與治療劑。於一些實施例中，每日投與為每天一次。於一些實施例中，每日投與為每天兩次。於一些實施例中，每日投與為每天三次。於一些實施例中，每日投與為每天大於三次。The term "continuous dosing schedule" refers to the administration of a particular therapeutic agent at regular intervals. In some embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent at regular intervals without any medication breaks from the particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to periodic administration of a particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to administration of a specific drug with a period of drug administration followed by a drug holiday from a specific therapeutic agent (eg, a washout period or other such time period when no drug is administered). therapeutic agent. For example, in some embodiments, once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week , every other day, every three days, every four days, administer the therapeutic agent every day for one week, then one week without the therapeutic agent, every day for two weeks, then one or two weeks without the therapeutic agent, every day Three weeks, followed by one, two, or three weeks with no therapeutic agent, daily for four weeks, followed by one, two, three, or four weeks with no therapeutic agent, weekly with no therapeutic agent, followed by one week The therapeutic agent, or the therapeutic agent is administered every two weeks followed by no therapeutic agent for two weeks. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice a day. In some embodiments, the daily administration is three times a day. In some embodiments, the daily administration is greater than three times per day.
術語「連續每日給藥時程表」係指在每天大致相同時間每天投與特定治療劑。於一些實施例中，每日投與為每天一次。於一些實施例中，每日投與為每天兩次。於一些實施例中，每日投與為每天三次。於一些實施例中，每日投與為每天大於三次。The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent each day at approximately the same time each day. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice a day. In some embodiments, the daily administration is three times a day. In some embodiments, the daily administration is greater than three times per day.
於一些實施例中，每天一次投與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之量。In some embodiments, the amount of FXR agonist (eg,
於某些實施例中，其中未觀察到人類之疾病或病狀之狀態的改善，增加FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之每日劑量。於一些實施例中，將每天一次給藥時程表改成每天兩次給藥時程表。於一些實施例中，採用每天三次給藥時程表增加投與之FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之量。於一些實施例中，增加藉由吸入之投與之頻率以提供更多定期重複高Cmax
含量。於一些實施例中，增加投與頻率以提供維持或更多定期暴露於FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。於一些實施例中，增加投與頻率以提供更多定期重複高Cmax含量且提供維持或更多定期暴露於FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)。In certain embodiments, wherein no improvement in the state of the disease or condition in humans is observed, the daily dose of an FXR agonist (eg,
於上述態樣中之任一者中，為包含有效量之FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之單一投與之另外實施例，包含另外實施例，其中(i)每天一次；或(ii)歷時一天跨度多次投與該FXR促效劑。In any of the above aspects, are additional embodiments comprising a single administration of an effective amount of an FXR agonist (eg,
於上述態樣中之任一者中，為包含有效量之FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之多重投與之另外實施例，包含另外實施例，其中(i)連續或間歇投與FXR促效劑：以單一劑量；(ii)多重投與之間之時間為每6小時；(iii)每8小時向哺乳動物投與FXR促效劑；(iv)每12小時向哺乳動物投與FXR促效劑；(v)每24小時向哺乳動物投與FXR促效劑。於另外或替代實施例中，該方法包括藥物假期，其中暫時停止FXR促效劑之投與或暫時減少正在投與之FXR促效劑之劑量；在藥物假期結束時，恢復FXR促效劑之給藥。於一個實施例中，藥物假期之長度自2天變成1年。In any of the above aspects, are additional embodiments comprising multiple administrations of an effective amount of an FXR agonist (eg,
一般而言，用於向人類投與之FXR促效劑之適宜劑量將於約0.01 mg/kg/天至約25 mg/kg/天之範圍內(例如，約0.2 mg/kg/天、約0.3 mg/kg/天、約0.4 mg/kg/天、約0.5 mg/kg/天、約0.6 mg/kg/天、約0.7 mg/kg/天、約0.8 mg/kg/天、約0.9 mg/kg/天、約1 mg/kg/天、約2 mg/kg/天、約3 mg/kg/天、約4 mg/kg/天、約5 mg/kg/天、約6 mg/kg/天、約7 mg/kg/天、約8 mg/kg/天、約9 mg/kg/天、約10 mg/kg/天、約15 mg/kg/天、約20 mg/kg/天或約25 mg/kg/天)。或者，用於向人類投與之FXR促效劑之適宜劑量將於約0.01 mg/天至約1000 mg/天；約1 mg/天至約400 mg/天；或約1 mg/天至約300 mg/天之範圍內。於其他實施例中，用於向人類投與之FXR促效劑之適宜劑量將為約5 mg/天、約10 mg/天、約15 mg/天、約20 mg/天、約25 mg/天、約30 mg/天、約35 mg/天、約40 mg/天、約45 mg/天、約50 mg/天、約55 mg/天、約60 mg/天、約65 mg/天、約70 mg/天、約75 mg/天、約80 mg/天、約85 mg/天、約90 mg/天、約95 mg/天、約100 mg/天、約125 mg/天、約150 mg/天、約175 mg/天、約200 mg/天、約225 mg/天、約250 mg/天、約275 mg/天、約300 mg/天、約325 mg/天、約350 mg/天、約375 mg/天、約400 mg/天、約425 mg/天、約450 mg/天、約475 mg/天或約500 mg/天。於一些實施例中，每天超過一次(例如，每天兩次、三次、四次或更多次)投與劑量。In general, a suitable dosage for administering an FXR agonist thereto to humans will be in the range of about 0.01 mg/kg/day to about 25 mg/kg/day (eg, about 0.2 mg/kg/day, about 0.3 mg/kg/day, about 0.4 mg/kg/day, about 0.5 mg/kg/day, about 0.6 mg/kg/day, about 0.7 mg/kg/day, about 0.8 mg/kg/day, about 0.9 mg /kg/day, about 1 mg/kg/day, about 2 mg/kg/day, about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 6 mg/kg /day, about 7 mg/kg/day, about 8 mg/kg/day, about 9 mg/kg/day, about 10 mg/kg/day, about 15 mg/kg/day, about 20 mg/kg/day or about 25 mg/kg/day). Alternatively, a suitable dosage for administering its FXR agonist to humans would be from about 0.01 mg/day to about 1000 mg/day; from about 1 mg/day to about 400 mg/day; or from about 1 mg/day to about within the range of 300 mg/day. In other embodiments, suitable dosages for administration of an FXR agonist thereto to a human would be about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, About 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, or about 500 mg/day. In some embodiments, the dose is administered more than once per day (eg, two, three, four or more times per day).
於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約1 mg/天至約300 mg/天。於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約5 mg/天至約150 mg/天。於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約5 mg/天至約100 mg/天。於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約5 mg/天至約80 mg/天。於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約5 mg/天至約50 mg/天。於一些實施例中，每天一次投與劑量。於一些實施例中，每天超過一次(例如，每天兩次、三次、四次或更多次)投與劑量。於一些實施例中，以上所提及之量係指化合物1之量。In some embodiments, a suitable dosage for administering
於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約5 mg/天、約10 mg/天、約15 mg/天、約20 mg/天、約25 mg/天、約30 mg/天、約35 mg/天、約40 mg/天、約45 mg/天、約50 mg/天、約55 mg/天、約60 mg/天、約65 mg/天、約70 mg/天、約75 mg/天、約80 mg/天、約85 mg/天、約90 mg/天、約95 mg/天、約100 mg/天、約125 mg/天或約150 mg/天。於一些實施例中，每天一次投與劑量。於一些實施例中，每天超過一次(例如，每天兩次、三次、四次或更多次)投與劑量。於一些實施例中，以上所提及之量係指化合物1之量。In some embodiments, suitable doses for administering
於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約50 mg/天。於一些實施例中，用於向人類投與之化合物1或其醫藥上可接受之鹽之適宜劑量為約80 mg/天。於一些實施例中，每天一次投與劑量。於一些實施例中，每天超過一次(例如，每天兩次、三次、四次或更多次)投與劑量。於一些實施例中，以上所提及之量係指化合物1之量。In some embodiments, a suitable dose for administering
於一些實施例中，呈劑型之活性劑之每日劑量或量高於或低於本文中所指定之範圍，基於關於個別治療方案之許多變量。於各種實施例中，每日及單位劑量取決於許多變量改變，該等變量包括(但不限於)待治療之疾病或病狀、投與模式、個別個體之要求、正在治療之疾病或病狀之嚴重度、人類之身份(例如，體重)、及投與之特定附加治療劑(若適用)、及實務者之判斷。In some embodiments, the daily dose or amount of active agent in dosage form is higher or lower than the ranges specified herein, based on a number of variables regarding the individual treatment regimen. In various embodiments, the daily and unit doses vary depending on a number of variables including, but not limited to, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the disease or condition being treated severity, human identity (eg, body weight), and administration of the particular additional therapeutic agent (if applicable), and the judgment of the practitioner.
此等治療方案之毒性及治療功效藉由細胞培養或實驗動物中之標準醫藥程序測定，包括(但不限於) LD50 及ED50 之測定。毒性與治療效應之間之劑量比率為治療指數及將其表示為LD50 與ED50 之間之比率。於某些實施例中，獲自細胞培養檢定及動物研究之資料係用於調配用於哺乳動物(包括人類)之治療上有效每日劑量範圍及/或治療上有效單位劑量。於一些實施例中，FXR促效劑之每日劑量位於循環濃度之範圍內，該等循環濃度包含具有最小毒性之ED50 。於某些實施例中，取決於採用之劑型及利用之投與途徑，每日劑量範圍及/或單位劑量於此範圍內變化。Toxicity and therapeutic efficacy of such treatment program by cell cultures or experimental animals of the assay standard pharmaceutical procedures, including (but not limited to) measurement of the LD 50 and ED 50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between the 50 LD 50 and ED. In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dosage ranges and/or therapeutically effective unit doses for mammals, including humans. In some embodiments, the daily dose of FXR agonist pro is within the range of circulating concentrations, circulating concentrations of these contain the ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and/or unit dose varies within this range depending upon the dosage form employed and the route of administration utilized.
於公開之臨床試驗中，OCA已顯示利用每日一次口服給藥總OCA (親本OCA加上其代謝物)之持續藥物含量及針對NAS及纖維化改善二者藉由肝活組織檢查量測之證明之臨床效益。然而，與OCA相關聯之搔癢限制於臨床試驗中使用更高劑量。此外，OCA特徵在於增加之LDL膽固醇及肝毒性之不利效應，其亦限制使用更高劑量。In published clinical trials, OCA has shown sustained drug content of total OCA (parental OCA plus its metabolites) with once-daily oral administration and improvement in both NAS and fibrosis as measured by liver biopsy proven clinical benefit. However, the itchiness associated with OCA has been limited to the use of higher doses in clinical trials. In addition, OCA is characterized by adverse effects of increased LDL cholesterol and hepatotoxicity, which also limit the use of higher doses.
於一些實施例中，向個體投與FXR促效劑引起搔癢。於一些實施例中，與FXR促效劑投與相關聯之搔癢在連續投與FXR促效劑下變得不嚴重或解決。於一些實施例中，與FXR促效劑投與相關聯之搔癢為劑量相關。於一些實施例中，最小化及/或解決與FXR促效劑投與相關聯之搔癢包括滴定投與之FXR促效劑之劑量。In some embodiments, administration of an FXR agonist to an individual causes itching. In some embodiments, the itching associated with FXR agonist administration becomes less severe or resolved with continuous administration of the FXR agonist. In some embodiments, the itchiness associated with FXR agonist administration is dose-related. In some embodiments, minimizing and/or resolving itchiness associated with administration of an FXR agonist comprises titrating the dose of the FXR agonist administered.
於一些實施例中，化合物1或其醫藥上可接受之鹽經由滴定時程表投與。於一些實施例中，化合物1或其醫藥上可接受之鹽經由滴定時程表投與以最小化與化合物1或其醫藥上可接受之鹽之投與相關聯之不良事件。於一些實施例中，利用化合物1或其醫藥上可接受之鹽滴定使：個體能耐受化合物1或其醫藥上可接受之鹽；最小化與化合物1或其醫藥上可接受之鹽之投與相關聯之不良事件；最大化化合物1或其醫藥上可接受之鹽之最佳劑量向個體投與及耐受的可能性；或其組合。於一些實施例中，滴定包括向上滴定。In some embodiments,
如本文中所用，若化合物之劑量向個體投與不導致不可接受之不良事件或不可接受之不良事件之組合，則稱該個體「耐受」該劑量。熟習此項技術者應瞭解，耐受為主觀量度及可對一名患者耐受者可對不同患者不耐受。例如，一個個體不可耐受搔癢，然而第二個個體可發現輕微搔癢耐受，但是不可耐受中度搔癢，然而第三個個體能耐受中度搔癢，但是不耐受嚴重搔癢。As used herein, a subject is said to "tolerate" a dose of a compound administered to an individual that does not result in an unacceptable adverse event or combination of unacceptable adverse events. Those skilled in the art will understand that tolerance is a subjective measure and what is tolerated by one patient may not be tolerated by a different patient. For example, one individual cannot tolerate itching, whereas a second individual may find mild itching tolerance, but not moderate itching, while a third individual can tolerate moderate itching, but not severe itching.
如本文中所用，「不良事件」為與利用化合物1或其醫藥上可接受之鹽治療相關聯之不幸醫療事件。於一些實施例中，不良事件為搔癢。As used herein, an "adverse event" is an unfortunate medical event associated with treatment with
如本文中所用，「最佳劑量」係指對特定個體之需求最佳化之治療劑量及為化合物1之最高劑量，或與化合物1之最高劑量等效之其醫藥上可接受之鹽之劑量，其引起個體之生物或醫療反應，該反應正在被尋找及可由個體耐受，如由個體所測定，視情況諮詢個體之健康護理實務者。As used herein, an "optimal dose" refers to a therapeutic dose optimized for the needs of a particular individual and is the highest dose of
如本文中所用，化合物之「向上滴定」係指增加化合物之量直至個體不耐受所增加之量。向上滴定可以一或多個劑量增量達成，該等增量可係相同或不同。於一些實施例中，該方法包括每日一次以初始劑量投與化合物1或其醫藥上可接受之鹽持續初始時間段，接著之後每日一次向上滴定至化合物1或其醫藥上可接受之鹽之更高劑量。於一些實施例中，該初始時間段包括一天、約1週、約2週、約3週、約4週、約5週、約6週、約7週、約8週、約9週、約10週、約11週或約12週。於一些實施例中，重複此循環直至達成最佳劑量。As used herein, "up titration" of a compound refers to increasing the amount of compound until the individual does not tolerate the increased amount. Up titration can be achieved in one or more dose increments, which increments can be the same or different. In some embodiments, the method comprises administering
於一些實施例中，該滴定方法包括每日一次以初始劑量投與化合物1或其醫藥上可接受之鹽持續約1週、約2週、約3週、約4週、約5週、約6週、約7週或約8週，接著之後每日一次向上滴定至化合物1或其醫藥上可接受之鹽之更高劑量。於一些實施例中，重複此循環直至達成最佳劑量。於一些實施例中，該方法包括以等效於約50 mg化合物1之量每日一次投與化合物1或其醫藥上可接受之鹽持續約1週、約2週、約3週、約4週、約5週、約6週、約7週或約8週，接著之後每日一次向上滴定至約80 mg化合物1或其醫藥上可接受之鹽。In some embodiments, the titration method comprises administering
於一些實施例中，該滴定方法包括化合物1或其醫藥上可接受之鹽、水合物或溶劑化物之向上滴定或向下滴定，接著視情況可選的再次向上滴定。In some embodiments, the titration method comprises up-titration or down-titration of
於一些實施例中，該滴定時程表包括以初始劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該初始劑量，以等於第一增量值之量增加該劑量或假如該患者不耐受該初始劑量，以等於第一增量值之量減少該劑量。In some embodiments, the titration schedule comprises administering
於一些實施例中，該初始劑量等效於約20 mg、30 mg、40 mg、50 mg、約60 mg、約70 mg、約80 mg、約90 mg、約100 mg、約110 mg、約120 mg、約130 mg、約140 mg、約150 mg或約160 mg化合物1。於一些實施例中，該初始劑量等效於約20 mg、30 mg、40 mg、50 mg、約60 mg、約70 mg或約80 mg化合物1。於一些實施例中，該初始劑量等效於約50 mg化合物1。於一些實施例中，該初始劑量等效於約80 mg化合物1。In some embodiments, the initial dose is equivalent to about 20 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg of
於一些實施例中，該滴定時程表進一步包括：以增加之劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該增加之劑量，以等於第二增量值之量進一步增加該劑量；或以減少之劑量投與化合物1或其醫藥上可接受之鹽或溶劑化物持續約1週及假如該患者耐受該減少之劑量，以等於第二增量值之量視情況增加該劑量。於一些實施例中，該第一增量值與該第二增量值相同。於一些實施例中，該第一增量值及該第二增量值係不同。In some embodiments, the titration schedule further comprises: administering
於一些實施例中，該第一增量值等效於約5 mg、10 mg、15 mg或約20 mg化合物1。於一些實施例中，該第二增量值等效於約5 mg、10 mg、15 mg或約20 mg化合物1。In some embodiments, the first incremental value is equivalent to about 5 mg, 10 mg, 15 mg, or about 20 mg of
於一些實施例中，重複該滴定時程表直至獲得最佳劑量。最佳劑量提供治療功效同時最小化利用FXR促效劑治療之副作用，諸如搔癢。In some embodiments, the titration schedule is repeated until an optimal dose is obtained. The optimal dose provides therapeutic efficacy while minimizing the side effects of treatment with FXR agonists, such as itching.
於一些實施例中，該最佳劑量為約30 mg、40 mg、50 mg、約60 mg、約70 mg、約80 mg、約90 mg、約100 mg、約110 mg、約120 mg、約130 mg、約140 mg、約150 mg或約160 mg化合物1。於一些實施例中，該最佳劑量為約50 mg化合物1。於一些實施例中，該最佳劑量為約80 mg化合物1。基於生物標誌物檢測之治療 In some embodiments, the optimal dose is about 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg of
於一些實施例中，包含至少一種FXR促效劑之醫藥組合物之投與係基於患者之循環FGF-19含量或基於組織之FGF-19含量。於一些實施例中，包含至少一種FXR促效劑及附加治療劑之組合之醫藥組合物之投與係基於患者之血清C4 (7α-羥基-4-膽烯-3-酮)含量。於一些實施例中，包含至少一種FXR促效劑及附加治療劑之組合之醫藥組合物之投與係基於患者之血清膽汁酸含量。於一些實施例中，包含至少一種FXR促效劑及附加治療劑之組合之醫藥組合物之投與係基於患者之糞便膽汁酸含量。於一些實施例中，該附加治療劑為抗纖維化治療劑、抗發炎劑、代謝治療劑、抗發炎劑、或本文中所述之其他治療劑中之任一者。於一些實施例中，向具有異常FGF-19、C4 (7α-羥基-4-膽烯-3-酮)或膽汁酸含量之患者投與含有本文中所述之組合療法之組合物。於一些實施例中，向具有異常FGF-19、C4 (7α-羥基-4-膽烯-3-酮)或膽汁酸含量之患者投與含有本文中所述之組合療法之組合物用於治療本文中所述之疾病或病狀中之任一者。作為預測 NASH 患者中對 FXR 療法之臨床反應之標誌物的肝脂肪含量 In some embodiments, the administration of a pharmaceutical composition comprising at least one FXR agonist is based on the patient's circulating FGF-19 levels or tissue-based FGF-19 levels. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's serum C4 (7α-hydroxy-4-cholen-3-one) levels. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's serum bile acid levels. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's fecal bile acid content. In some embodiments, the additional therapeutic agent is an anti-fibrotic therapeutic agent, an anti-inflammatory agent, a metabolic therapeutic agent, an anti-inflammatory agent, or any of the other therapeutic agents described herein. In some embodiments, patients with abnormal FGF-19, C4 (7α-hydroxy-4-cholen-3-one), or bile acid levels are administered a composition containing a combination therapy described herein. In some embodiments, a patient with abnormal FGF-19, C4 (7α-hydroxy-4-cholen-3-one), or bile acid levels is administered a composition containing the combination therapy described herein for treatment Any of the diseases or conditions described herein. Liver fat content as a predictor of clinical response to FXR therapy in NASH patients
當評價針對NASH之治療形式時，證明跨發炎、球囊擴張及纖維化之顯著臨床受益具有挑戰性。臨床試驗之功效通常藉由顯示NAS之改善或解決或纖維化之逆轉來證明。此等終點二者之明確評估通常需要肝活組織檢查；然而，非侵入性成像及生物標誌物越來越多地用於評估，因為其與肝活組織檢查之發現結果相關。若干研究已顯示藉由非侵入性成像量測之患者之肝脂肪自基線減少至少30%係與肝活組織檢查之臨床改善相關。因此，通常使用於早期NASH臨床試驗中使用非侵入性成像以評價肝脂肪變化。When evaluating treatment modalities for NASH, demonstrating significant clinical benefit across inflammation, balloon dilation and fibrosis is challenging. Efficacy in clinical trials is usually demonstrated by showing improvement or resolution of NAS or reversal of fibrosis. Definitive assessment of both of these endpoints typically requires liver biopsy; however, non-invasive imaging and biomarkers are increasingly used for assessment as they correlate with liver biopsy findings. Several studies have shown that at least a 30% reduction in liver fat from baseline in patients measured by non-invasive imaging correlates with clinical improvement on liver biopsy. Therefore, non-invasive imaging is commonly used in early NASH clinical trials to evaluate liver fat changes.
對開發可幫助指導NASH之治療策略之可用診斷性測試存在需求，該等策略包括投與FXR促效劑。於一些實施例中，精確評估包含FXR促效劑之NASH治療策略提供有用資訊，諸如(但不限於)：患者對FXR促效劑之反應；利用FXR促效劑治療NASH之適當性；利用FXR促效劑可能之最大效應；針對最大效應所需之FXR促效劑之劑量；所需FXR促效劑之劑量調整；利用FXR促效劑之療法之持續時間；及/或組合療法是否於個別患者中所需。對FXR促效劑之反應之早期預測可幫助指導利用FXR促效劑之長期治療策略。There is a need to develop useful diagnostic tests that can help guide treatment strategies for NASH, including the administration of FXR agonists. In some embodiments, accurate assessment of NASH treatment strategies comprising FXR agonists provides useful information such as (but not limited to): patient response to FXR agonists; appropriateness of treatment of NASH with FXR agonists; utilization of FXR The maximal effect of the agonist; the dose of FXR agonist required for maximal effect; the dose adjustment of the FXR agonist required; the duration of therapy with the FXR agonist; and/or whether the combination therapy required in patients. Early prediction of response to FXR agonists can help guide long-term treatment strategies utilizing FXR agonists.
於一些實施例中，使用磁共振成像-質子密度脂肪分數(MRI-PDFF)之肝脂肪含量(LFC)測量係用於預測利用FXR促效劑治療之NASH患者長期之肝脂肪含量變化之量級。於一些實施例中，LFC變化為對利用FXR促效劑治療之反應之重要預測因素。於一些實施例中，使用磁共振成像-質子密度脂肪分數(MRI-PDFF)之肝脂肪含量(LFC)測量之變化與接受者操作特徵下面積(AUC)分析組合係用於預測利用FXR促效劑治療之NASH患者長期之LFC變化。於一些實施例中，該FXR促效劑為本文中所述之FXR促效劑。於一些實施例中，該FXR促效劑為化合物1或其醫藥上可接受之鹽。In some embodiments, liver fat content (LFC) measurement using Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) is used to predict the magnitude of long-term changes in liver fat content in NASH patients treated with FXR agonists . In some embodiments, LFC change is an important predictor of response to treatment with an FXR agonist. In some embodiments, changes in liver fat content (LFC) measurements using Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) in combination with area under receiver operating characteristic (AUC) analysis are used to predict potentiation with FXR Long-term LFC changes in drug-treated NASH patients. In some embodiments, the FXR agonist is an FXR agonist described herein. In some embodiments, the FXR agonist is
於一些實施例中，於利用FXR促效劑治療約4週後肝脂肪含量(LFC)減少精確預測於利用FXR促效劑治療約12週後觀察到之肝脂肪含量(LFC)減少。於一些實施例中，在約12週時預測之LFC減少至少與在治療約4週時觀察到之LFC減少一樣多。於一些實施例中，在約12週時預測之LFC減少大於在治療約4週時觀察到之LFC減少。於一些實施例中，利用FXR促效劑治療包括FXR促效劑之連續每日給藥。於一些實施例中，該FXR促效劑為本文中所述之FXR促效劑。於一些實施例中，該FXR促效劑為化合物1或其醫藥上可接受之鹽。組合療法 In some embodiments, the reduction in liver fat content (LFC) after about 4 weeks of treatment with the FXR agonist accurately predicts the reduction in liver fat content (LFC) observed after about 12 weeks of treatment with the FXR agonist. In some embodiments, the predicted reduction in LFC at about 12 weeks is at least as great as the LFC reduction observed at about 4 weeks of treatment. In some embodiments, the predicted reduction in LFC at about 12 weeks is greater than the observed reduction in LFC at about 4 weeks of treatment. In some embodiments, treatment with an FXR agonist includes continuous daily administration of the FXR agonist. In some embodiments, the FXR agonist is an FXR agonist described herein. In some embodiments, the FXR agonist is
於某些實例中，適宜投與本文中所述之至少一種FXR促效劑或其醫藥上可接受之鹽與一或多種其他治療劑組合。In certain instances, it is suitable to administer at least one FXR agonist described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.
於一個實施例中，本文中所述化合物中之一者之治療有效性藉由投與佐劑增強(即，佐劑自身具有最小治療效益，但是與另一治療劑組合，對患者之總體治療效益增強)。或，於一些實施例中，患者所經歷之效益藉由投與本文中所述化合物中之一者與亦具有治療效益之另一藥劑(其亦包含治療方案)增加。In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (ie, the adjuvant itself has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall treatment of the patient) benefit enhancement). Or, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.
於一個特定實施例中，本文中所述化合物或其醫藥上可接受之鹽與第二治療劑共同投與，其中本文中所述化合物或其醫藥上可接受之鹽及該第二治療劑調節正在治療之疾病、病症或病狀之不同態樣，從而提供較單獨投與任一治療劑更大總體效益。In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate Different aspects of the disease, disorder or condition being treated, thereby providing greater overall benefit than administration of either therapeutic agent alone.
於任一情況下，不管正在治療之疾病、病症或病狀，於一些實施例中，患者所經歷之總體效益為兩種治療劑之加成或患者經歷協同效益。In either case, regardless of the disease, disorder, or condition being treated, in some embodiments, the overall benefit experienced by the patient is the addition of the two therapeutic agents or the patient experiences a synergistic benefit.
於某些實施例中，當本文中所揭示之化合物與一或多種附加劑(諸如附加藥物、佐劑或類似者)組合投與時，本文中所揭示化合物之不同劑量將於調配醫藥組合物中及/或於治療方案中利用。用於組合治療方案之藥物及其他劑之劑量視情況藉由與上文中針對活性自身所闡述之彼等相似之方式測定。此外，本文中所述之預防/治療方法包括使用節拍式給藥，即，提供更頻繁更低劑量以最小化毒性副作用。於一些實施例中，組合治療方案包括治療方案，其中本文中所述化合物或其醫藥上可接受之鹽之投與在利用本文中所述之第二劑治療之前、期間或之後開始，及繼續直至利用第二劑治療期間或於終止利用第二劑治療後之任何時間。其亦包括治療，其中本文中所述化合物或其醫藥上可接受之鹽及組合使用之第二劑同時或在不同時間及/或在治療期期間以減少或增加間隔投與。組合治療進一步包括週期性治療，其在各種時間開始及停止以幫助患者之臨床管理。In certain embodiments, when the compounds disclosed herein are administered in combination with one or more additional agents, such as additional drugs, adjuvants, or the like, different dosages of the compounds disclosed herein will formulate pharmaceutical compositions In and/or use in treatment regimens. Dosages of drugs and other agents for combination therapy regimens are optionally determined in a manner similar to those described above for the activity itself. In addition, the methods of prevention/treatment described herein include the use of metronomic dosing, ie, providing more frequent lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen includes a treatment regimen wherein administration of a compound described herein, or a pharmaceutically acceptable salt thereof, begins before, during, or after treatment with a second dose described herein, and continues Until during treatment with the second dose or at any time after cessation of treatment with the second dose. It also includes therapy wherein a compound described herein, or a pharmaceutically acceptable salt thereof, and a second dose in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination therapy further includes periodic therapy that starts and stops at various times to aid in the clinical management of the patient.
針對本文中所述之組合療法，共同投與之化合物之劑量取決於採用之共治療劑之類型、採用之特定治療劑、正在治療之疾病或病狀等等變化。於另外實施例中，當與一或多種其他治療劑共同投與時，本文中所提供之化合物與一或多種其他治療劑同時或依序投與。For the combination therapy described herein, the dose of the co-administered compound will vary depending on the type of co-therapeutic agent employed, the particular therapeutic agent employed, the disease or condition being treated, and the like. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered concurrently or sequentially with one or more other therapeutic agents.
於組合療法中，多種治療劑(其中之一者為本文中所述化合物中之一者)以任何順序或甚至同時投與。若投與係同時，則多種治療劑(僅舉例而言)以單一統一形式或以多種形式(例如，呈單一丸劑或呈兩個分開丸劑)提供。In combination therapy, multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. If the administration is simultaneous, the multiple therapeutic agents (by way of example only) are provided in a single unified form or in multiple forms (eg, in a single bolus or in two separate boluses).
本文中所述化合物或其醫藥上可接受之鹽以及組合療法在疾病或病狀發生之前、期間或之後投與，及投與含有化合物之組合物之時間變化。因此，於一個實施例中，本文中所述化合物係用作預防劑及向具有發展病狀或疾病之傾向之哺乳動物連續投與以預防該疾病或病狀之發生。於另一實施例中，該等化合物及組合物在症狀發作期間或於症狀發作後儘快向哺乳動物投與。The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, as well as the timing of administration of compositions containing the compounds. Thus, in one embodiment, the compounds described herein are used as prophylactics and administered continuously to a mammal having a propensity to develop a condition or disease to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to the mammal during the onset of symptoms or as soon as possible after the onset of symptoms.
於預防性應用中，含有本文中所述之組合療法之組合物向易感或原本具有特定疾病、病症或病狀之風險之患者投與。此量經定義為「預防上有效量或劑量」。於此用途中，精確量亦取決於患者之健康狀態、體重及類似者。當於患者中使用時，針對此用途之有效量將取決於疾病、病症或病狀之嚴重度及過程、先前療法、患者之健康狀態及對藥物之反應、及治療醫師之判斷。於一個態樣中，預防性治療包括向先前經歷正在治療之疾病之至少一種症狀及目前緩解之哺乳動物投與包含本文中所述化合物或其醫藥上可接受之鹽之醫藥組合物以預防疾病或病狀之症狀之復發。In prophylactic applications, compositions containing the combination therapies described herein are administered to patients susceptible or otherwise at risk for a particular disease, disorder, or condition. This amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's state of health, weight, and the like. When used in a patient, an effective amount for this use will depend on the severity and course of the disease, disorder or condition, prior therapy, the patient's state of health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering to a mammal who has previously experienced at least one symptom of and is currently in remission of the disease being treated, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to prevent the disease or recurrence of symptoms of the condition.
於某些實施例中，本文中所述之FXR促效劑及附加治療劑以較FXR促效劑或附加治療劑作為單藥療法劑正常投與之劑量更低劑量投與。於某些實施例中，本文中所述之FXR促效劑及附加治療劑以較FXR促效劑或附加治療劑正常投與之劑量更低劑量投與以證明功效。於某些實施例中，當與本文中所述之附加治療劑組合投與時，FXR促效劑以較其作為單藥療法劑正常投與之劑量更低劑量投與。於某些實施例中，當與本文中所述之附加治療劑組合投與時，FXR促效劑以較其正常投與之劑量更低劑量投與以證明功效。於某些實施例中，當與FXR促效劑組合投與時，附加治療劑以較其作為單藥療法劑正常投與之劑量更低劑量投與。於某些實施例中，當與FXR促效劑組合投與時，附加治療劑以較其正常投與之劑量更低劑量投與以證明功效。In certain embodiments, the FXR agonists and additional therapeutic agents described herein are administered at lower doses than the FXR agonists or additional therapeutic agents would normally be administered as a monotherapy. In certain embodiments, the FXR agonists and additional therapeutic agents described herein are administered at lower doses to demonstrate efficacy than are normally administered with the FXR agonist or additional therapeutic agent. In certain embodiments, when administered in combination with an additional therapeutic agent described herein, the FXR agonist is administered at a lower dose than it would normally be administered as a monotherapy agent. In certain embodiments, when administered in combination with an additional therapeutic agent described herein, the FXR agonist is administered at a lower dose than it would normally be administered to demonstrate efficacy. In certain embodiments, when administered in combination with an FXR agonist, the additional therapeutic agent is administered at a lower dose than it would normally be administered as a monotherapy. In certain embodiments, when administered in combination with an FXR agonist, the additional therapeutic agent is administered at a lower dose than it would normally be administered to demonstrate efficacy.
於本文中所述實施例中之任一者中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)係用於包含一或多種附加治療劑之治療方案中。於本文中所述實施例中之任一者中，該FXR促效劑與如本文中所述之任何附加治療劑使用。例如，於一些實施例中，該附加治療劑為小分子、大分子、寡核苷酸、病毒、細菌、抗發炎劑、免疫調節劑、抗癌劑、體重損失、治療NASH之劑、治療糖尿病之劑、治療胰島素抗性之劑、他汀、胰島素增敏劑、維生素、抗真菌劑、抗氧化劑、皮質類固醇、抗腫瘤壞死因子(TNF)劑、抗生素、化療劑、生物劑、放射療法劑、抗肥胖劑、營養劑、放射療法或治療原發性膽汁性膽管炎之劑。In any of the embodiments described herein, an FXR agonist (eg,
於一些實施例中，脂肪肝病(諸如但不限於NAFLD及NASH)之治療包括利用FXR促效劑化合物(例如，化合物1或其醫藥上可接受之鹽)及用於治療脂肪肝病之至少一種附加劑之組合療法。FXR促效劑同時解決NASH之多種發病機理，包括脂肪變性、發炎及纖維化，其解決脂肪肝病之代謝性及纖維化要素，從而使FXR促效劑為理想基礎療法以與用於脂肪肝病之其他治療組合使用。例如，鈉-葡萄糖轉運蛋白2或SGLT2抑制劑表示治療糖尿病之一類口服藥物，其在腎中之葡萄糖轉運蛋白上起作用。臨床試驗已顯示SGLT2抑制劑可改善葡萄糖控制，改善胰島素敏感性，導致體重損失及減少主要不良心血管事件。此外，利用SGLT2抑制劑之概念驗證研究顯示改善糖尿病性NASH患者中之肝脂肪及肝酶之能力。於一些實施例中，SGLT2抑制劑可以與由FXR促效劑提供者互補之方式改善NASH。In some embodiments, treatment of fatty liver disease (such as, but not limited to, NAFLD and NASH) includes the use of an FXR agonist compound (eg,
於一些實施例中，FXR促效劑與下列標靶蛋白中之任一者之調節劑一起投與：***素受體1、***素受體2、過氧物酶體增殖物活化受體(PPAR)-δ、PPAR γ、PPAR α、PPAR α及PPAR δ (雙重調節)、smoothened受體(SMO)、Hedgehog信號效應子(諸如Gli-1及Gli-2)、Yes相關聯之蛋白(YAP)、具有PDZ結合基序之轉錄共活化子(TAZ)、熱激蛋白47 (HSP47)、膠原1型α1 (COL1A1)、轉化生長因子(TGF)-β、α-5 β-6整合素、血小板源性生長因子(PDGF)、頂端鈉–膽汁酸轉運蛋白(ASBT)、C-C趨化因子受體2型(CCR2)、C-C趨化因子受體5型(CCR5)、雙重C-C趨化因子受體2型/ C-C趨化因子受體5型(CCR 2/5)、溶血磷脂酸受體(LPA)-1、自分泌運動因子(autotaxin)、細胞凋亡信號調節激酶1 (ASK1)、NADPH氧化酶1 (NOX1)、NADPH氧化酶4 (NOX4)、NADPH氧化酶2 (NOX2)、NADPH氧化酶5 (NOX5)、雙重氧化酶1 (DUOX1)、雙重氧化酶2 (DUOX2)、半胱天冬酶、半乳凝素3、穿透素-2、乙醯基CoA羧酶、類升糖素胜肽-1 (GLP-1)、可誘導一氧化氮合成酶(iNOS)、N-乙醯半胱胺酸、S-腺苷基-甲硫胺酸、離胺醯氧化酶(LOXL2)、血管收縮素2受體、含溴結構域蛋白4 (BRD4)、真核轉譯起始因子4E (eIF4E)、血管內皮生長因子(VEGF)、纖維母細胞活化蛋白、維生素D受體、類鐸受體4 (TLR4)、TIMP金屬肽酶抑制劑1 (TIMP-1)、C-X-C趨化因子受體3型(CXCR3)、介白素-13 (IL-13)、IL-4、α v β 3整合素、纖維母細胞生長因子19、纖維母細胞生長因子21、ABCA1/SCD1、甲狀腺激素受體(THR) β、二醯基甘油醯基轉移酶1 (DGAT-1)、二醯基甘油醯基轉移酶2 (DGAT-2)、盤狀結構域受體1 (DDR1)、盤狀結構域受體(DDR2)、黏著斑激酶(FAK)、胺基脲敏感性胺氧化酶(SSAO/VAP-1)、17b-HSD 13型、GPR84、蛋白酶活化受體(PAR-2)或視黃酸受體相關孤兒受體γt (RORγt)。In some embodiments, the FXR agonist is administered with a modulator of any of the following target proteins: cannabinoid receptor 1, cannabinoid receptor 2, peroxisome proliferator-activated receptor ( PPAR)-delta, PPAR gamma, PPAR alpha, PPAR alpha and PPAR delta (dual regulation), smoothened receptor (SMO), Hedgehog signaling effectors such as Gli-1 and Gli-2, Yes associated protein (YAP) ), transcriptional coactivator (TAZ) with PDZ binding motif, heat shock protein 47 (HSP47), collagen type 1 alpha1 (COL1A1), transforming growth factor (TGF)-beta, alpha-5 beta-6 integrin, Platelet-derived growth factor (PDGF), apical sodium-bile acid transporter (ASBT), CC chemokine receptor type 2 (CCR2), CC chemokine receptor type 5 (CCR5), dual CC chemokine receptor Body type 2/CC chemokine receptor type 5 (CCR 2/5), lysophosphatidic acid receptor (LPA)-1, autotaxin, apoptosis signal-regulated kinase 1 (ASK1), NADPH Oxidase 1 (NOX1), NADPH Oxidase 4 (NOX4), NADPH Oxidase 2 (NOX2), NADPH Oxidase 5 (NOX5), Dual Oxidase 1 (DUOX1), Dual Oxidase 2 (DUOX2), Cysteine Asparase, Galectin-3, Penetrin-2, Acetyl-CoA Carboxylase, Glucagon-Like Peptide-1 (GLP-1), Inducible Nitric Oxide Synthase (iNOS), N-acetyl Cysteine, S-adenosyl-methionine, lysine oxidase (LOXL2), angiotensin 2 receptor, bromodomain-containing protein 4 (BRD4), eukaryotic translation initiation factor 4E (eIF4E), Vascular Endothelial Growth Factor (VEGF), Fibroblast Activating Protein, Vitamin D Receptor, Torroid Receptor 4 (TLR4), TIMP Metallopeptidase Inhibitor 1 (TIMP-1), CXC Chemokine Receptor Body type 3 (CXCR3), interleukin-13 (IL-13), IL-4, α v β 3 integrin, fibroblast growth factor 19, fibroblast growth factor 21, ABCA1/SCD1, thyroid hormone receptor Body (THR) β, Diacylglycerolyltransferase 1 (DGAT-1), Diacylglycerolyltransferase 2 (DGAT-2), Discoid Domain Receptor 1 (DDR1), Discoid Domain Receptor (DDR2), Focal Adhesion Kinase (FAK), Semicarbazide-Sensitive Amine Oxidase (SSAO/VAP-1), 17b-HSD Type 13, GPR84, Protease Activated Receptor (PAR-2) or Retinoid Acid receptor-related orphan receptor γt (RORγt).
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與下列標靶蛋白中之任一者之調節劑組合投與：***素受體1、***素受體2、過氧物酶體增殖物活化受體(PPAR)-δ、PPAR γ、PPAR α、PPAR α及PPAR δ (雙重調節)、熱激蛋白47 (HSP47)、纖維母細胞生長因子19、纖維母細胞生長因子21、轉化生長因子(TGF)-β、頂端鈉–膽汁酸轉運蛋白(ASBT)、ABCA1/SCD1、C-C趨化因子受體2型(CCR2)、C-C趨化因子受體5型(CCR5)、雙重C-C趨化因子受體2型/ C-C趨化因子受體5型(CCR 2/5)、溶血磷脂酸受體(LPA)-1、自分泌運動因子、細胞凋亡信號調節激酶1 (ASK1)、半胱天冬酶、乙醯基CoA羧酶(ACC)、類升糖素胜肽-1 (GLP-1)、N-乙醯半胱胺酸、S-腺苷基-甲硫胺酸、離胺醯氧化酶(LOXL2)、血管收縮素2受體、血管內皮生長因子(VEGF)、纖維母細胞活化蛋白、甲狀腺激素受體(THR) β、二醯基甘油醯基轉移酶1 (DGAT-1)、二醯基甘油醯基轉移酶2 (DGAT-2)、盤狀結構域受體1 (DDR1)、盤狀結構域受體(DDR2)、黏著斑激酶(FAK)、胺基脲敏感性胺氧化酶(SSAO/VAP-1)、17b-HSD 13型、GPR84、蛋白酶活化受體(PAR-2)、視黃酸受體相關孤兒受體γt (RORγt)。In some embodiments, an FXR agonist (eg, Compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a modulator of any of the following target proteins: Cannabinoid receptor 1, Cannabinoid receptor 1 Body 2, peroxisome proliferator-activated receptor (PPAR)-delta, PPAR gamma, PPAR alpha, PPAR alpha and PPAR delta (dual regulation), heat shock protein 47 (HSP47), fibroblast growth factor 19, Fibroblast growth factor 21, transforming growth factor (TGF)-β, apical sodium-bile acid transporter (ASBT), ABCA1/SCD1, CC chemokine receptor type 2 (CCR2), CC chemokine receptor 5 type (CCR5), dual CC chemokine receptor type 2/CC chemokine receptor type 5 (CCR 2/5), lysophosphatidic acid receptor (LPA)-1, autotaxin, apoptosis signaling Regulatory Kinase 1 (ASK1), Caspase, Acetyl-CoA Carboxylase (ACC), Glucagon-Like Peptide-1 (GLP-1), N-Acetylcysteine, S-Adenosine L-methionine, lysine oxidase (LOXL2), angiotensin 2 receptor, vascular endothelial growth factor (VEGF), fibroblast-activated protein, thyroid hormone receptor (THR) beta, diacylglycerol Acyltransferase 1 (DGAT-1), diacylglyceroyltransferase 2 (DGAT-2), discoid domain receptor 1 (DDR1), discoid domain receptor (DDR2), focal adhesion kinase (FAK), aminourea-sensitive amine oxidase (SSAO/VAP-1), 17b-HSD type 13, GPR84, protease-activated receptor (PAR-2), retinoic acid receptor-related orphan receptor γt (RORγt ).
於一些實施例中，FXR促效劑與下列標靶蛋白中之任一者之調節劑一起投與：血管收縮素2型受體、酮己糖激酶(KHK)、粒線體解偶聯劑或質子載體、鈉-葡萄糖轉運蛋白2 (SGLT2)、鈉-葡萄糖轉運蛋白1 (SGLT1)、二氫神經醯胺去飽和酶1 (DES-1)、整合素aVb1、整合素aVb6、類NOD受體蛋白3 (NLRP3)、親環素、類升糖素胜肽-1 (GLP-1)、17-β-羥基類固醇脫氫酶13型(17b-HSD 13型)、甲狀腺激素受體β (THR-beta)或其組合。In some embodiments, the FXR agonist is administered with a modulator of any of the following target proteins:
於一些實施例中，FXR促效劑與下列中之任一者一起投與：血管收縮素2型受體促效劑、KHK抑制劑、粒線體解偶聯劑或質子載體、SGLT2抑制劑、SGLT1/2共抑制劑、DES-1抑制劑、整合素aVb1抑制劑、整合素aVb6抑制劑、NLRP3抑制劑、親環素抑制劑、GLP-1促效劑、17b-HSD 13型抑制劑、THR-β促效劑或其組合。In some embodiments, the FXR agonist is administered with any of the following: an
於本文中所述實施例中之任一者中，該附加治療劑為用於治療代謝性疾病或病狀之劑。於本文中所述實施例中之任一者中，該附加治療劑為用於治療纖維化疾病或病狀之劑。於一些實施例中，該用於治療纖維化疾病或病狀之附加治療劑為吡非尼酮(pirfenidone)。In any of the embodiments described herein, the additional therapeutic agent is an agent for treating a metabolic disease or condition. In any of the embodiments described herein, the additional therapeutic agent is an agent for treating a fibrotic disease or condition. In some embodiments, the additional therapeutic agent for treating a fibrotic disease or condition is pirfenidone.
於一些實施例中，結合FXR促效劑投與作為治療或預防有需要個體之肝病(包括但不限於纖維化肝病或代謝性肝病)之方法之部分的附加治療劑為抗纖維化治療劑、抗發炎劑或代謝治療劑。In some embodiments, the additional therapeutic agent administered in conjunction with an FXR agonist as part of a method of treating or preventing liver disease (including but not limited to fibrotic liver disease or metabolic liver disease) in an individual in need thereof is an anti-fibrotic therapeutic agent, Anti-inflammatory or metabolic therapeutics.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與以下組合投與：***素受體1拮抗劑、smoothened受體(SMO)拮抗劑、Yes相關聯之蛋白(YAP)、PDZ結合基序(TAZ)拮抗劑、熱激蛋白47 (HSP47)拮抗劑、膠原1型α1 (COL1a1)拮抗劑、轉化生長因子-β (TGF-β)拮抗劑、α-5 β-6整合素拮抗劑、吡非尼酮、血小板源性生長因子(PDGF)拮抗劑、C-C趨化因子受體2型及5型(CCR2/CCR5)拮抗劑、溶血磷脂酸受體-1 (LPA-1)拮抗劑、自分泌運動因子拮抗劑、細胞凋亡信號調節激酶1 (ASK1)拮抗劑、類升糖素胜肽-1 (GLP-1)促效劑、過氧物酶體增殖物活化受體(PPAR)-δ促效劑、PPAR γ促效劑、PPAR α促效劑、PPAR α及PPAR δ雙重促效劑、乙醯基CoA羧酶(ACC)抑制劑、纖維母細胞生長因子19類似物、纖維母細胞生長因子21類似物、ABCA1/SCD1調節劑、甲狀腺激素受體(THR) β促效劑、二醯基甘油醯基轉移酶1 (DGAT-1)抑制劑、二醯基甘油醯基轉移酶2 (DGAT-2)抑制劑、盤狀結構域受體1 (DDR1)抑制劑、盤狀結構域受體(DDR2)抑制劑、黏著斑激酶(FAK)抑制劑、胺基脲敏感性胺氧化酶(SSAO/VAP-1)抑制劑、17b-HSD 13型抑制劑、GPR84拮抗劑、蛋白酶活化受體(PAR-2)拮抗劑或視黃酸受體相關孤兒受體γt (RORγt)拮抗劑/反向促效劑、NADPH氧化酶1 (NOX1)拮抗劑、NOX2拮抗劑、雙重NOX1/NOX4拮抗劑、NOX5拮抗劑、DUOX1拮抗劑、DUOX2拮抗劑、NOX4拮抗劑、半胱天冬酶拮抗劑、半乳凝素3拮抗劑、可誘導一氧化氮合成酶(iNOS)拮抗劑、N-乙醯半胱胺酸、離胺醯氧化酶同源物2 (LOXL2)拮抗劑、血管收縮素2受體拮抗劑、含溴結構域蛋白4 (BRD4)抑制劑、真核轉譯起始因子4E (eIF4E)拮抗劑、***素受體2促效劑、血管內皮生長因子(VEGF)促效劑、VEGF拮抗劑、纖維母細胞活化蛋白拮抗劑、維生素D受體拮抗劑、類鐸受體4 (TLR4)拮抗劑、金屬蛋白酶組織抑制劑-1 (TIMP-1)拮抗劑、熊去氧膽酸或非熊去氧膽酸。與趨化因子受體 (CCR) 抑制劑組合 In some embodiments, the FXR agonist (eg, Compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with: Cannabinoid receptor 1 antagonist, smoothened receptor (SMO) antagonist, Yes associated protein (YAP), PDZ-binding motif (TAZ) antagonists, heat shock protein 47 (HSP47) antagonists, collagen type 1 alpha1 (COL1a1) antagonists, transforming growth factor-beta (TGF-beta) antagonists, alpha -5 β-6 integrin antagonist, pirfenidone, platelet-derived growth factor (PDGF) antagonist, CC chemokine receptor type 2 and 5 (CCR2/CCR5) antagonist, lysophosphatidic acid receptor -1 (LPA-1) antagonist, autotaxin antagonist, apoptosis signal-regulated kinase 1 (ASK1) antagonist, glucagon-like peptide-1 (GLP-1) agonist, peroxygen Proliferator-activated receptor (PPAR)-delta agonists, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and PPAR delta dual agonists, acetyl CoA carboxylase (ACC) inhibitors, Fibroblast growth factor 19 analogs, fibroblast growth factor 21 analogs, ABCA1/SCD1 modulators, thyroid hormone receptor (THR) beta agonists, diacylglycerosyltransferase 1 (DGAT-1) Inhibitors, Diglyceryltransferase 2 (DGAT-2) Inhibitors, Discoid Domain Receptor 1 (DDR1) Inhibitors, Discoid Domain Receptor (DDR2) Inhibitors, Focal Adhesion Kinase (FAK) ) inhibitors, aminourea-sensitive amine oxidase (SSAO/VAP-1) inhibitors, 17b-HSD type 13 inhibitors, GPR84 antagonists, protease-activated receptor (PAR-2) antagonists or retinoic acid receptors Body-related orphan receptor γt (RORγt) antagonists/inverse agonists, NADPH oxidase 1 (NOX1) antagonists, NOX2 antagonists, dual NOX1/NOX4 antagonists, NOX5 antagonists, DUOX1 antagonists, DUOX2 antagonists , NOX4 antagonist, caspase antagonist, galectin 3 antagonist, inducible nitric oxide synthase (iNOS) antagonist, N-acetylcysteine, lysine oxidase homolog 2 (LOXL2) antagonists, angiotensin 2 receptor antagonists, bromodomain-containing protein 4 (BRD4) inhibitors, eukaryotic translation initiation factor 4E (eIF4E) antagonists, cannabinoid receptor 2 agonists , Vascular endothelial growth factor (VEGF) agonists, VEGF antagonists, fibroblast-activated protein antagonists, vitamin D receptor antagonists, toll-like receptor 4 (TLR4) antagonists, tissue inhibitor of metalloproteinase-1 ( TIMP-1) antagonist, ursodeoxycholic acid or non-ursodeoxycholic acid. In combination with chemokine receptor (CCR) inhibitors
發炎性單核細胞及巨噬細胞經由趨化因子受體2型(CCR2)以及淋巴細胞及肝星狀細胞經由趨化因子受體5型(CCR5)之募集促進NASH進展成纖維化。The recruitment of inflammatory monocytes and macrophages via chemokine receptor type 2 (CCR2) and lymphocytes and hepatic stellate cells via chemokine receptor type 5 (CCR5) promote the progression of NASH to fibrosis.
脂肪及肝組織之肥胖相關聯之巨噬細胞浸潤由趨化因子受體2型(CCR2)介導，其中CCR2陽性、CD11b陽性、F4/80陽性巨噬細胞促進慢性發炎及胰島素抗性。Obesity-associated macrophage infiltration of adipose and liver tissue is mediated by chemokine receptor type 2 (CCR2), wherein CCR2-positive, CD11b-positive, F4/80-positive macrophages promote chronic inflammation and insulin resistance.
若干研究已強調CCR2及CCR5於發炎及纖維化中之重要性。於一些實施例中，CCR2及/或CCR5之抑制劑與對照個體相比提高胰島素敏感性及葡萄糖耐受，降低ALT濃度及肝甘油三酯含量，提高胰島素敏感性或其組合。Several studies have emphasized the importance of CCR2 and CCR5 in inflammation and fibrosis. In some embodiments, inhibitors of CCR2 and/or CCR5 increase insulin sensitivity and glucose tolerance, decrease ALT concentrations and hepatic triglyceride levels, increase insulin sensitivity, or a combination thereof, compared to control subjects.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與CCR抑制劑組合投與。於一些實施例中，該CCR抑制劑為CCR2抑制劑、CCR5抑制劑、或CCR2及CCR5之雙重抑制劑。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與CCR2抑制劑、CCR5抑制劑、或CCR2及CCR5之雙重抑制劑組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與CCR2抑制劑組合投與。於一些實施例中，該CCR2抑制劑為CCX872。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與CCR2及CCR5之雙重抑制劑組合投與。於一些實施例中，CCR2及CCR5之雙重抑制劑為塞尼韋羅(cenicriviroc)。 與 ASK-1 抑制劑組合 In some embodiments, an FXR agonist (eg,
細胞凋亡信號調節激酶1 (ASK-1)為MAP激酶信號轉導路徑之基本組分。ASK-1活化下游c-Jun N-端激酶(JNK)及p38 MAP激酶，其誘導發炎性細胞激素之產生及細胞凋亡。於肝病(諸如NAFLD)中，JNK藉由ASK-1之活化誘導TGF-β介導之肝細胞之細胞凋亡。因此，阻斷、抑制、減少或抑制ASK-1提供一種治療或預防有需要個體之肝病之方法。 於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與ASK-1抑制劑組合投與。於一些實施例中，該ASK-1抑制劑為司隆色替(selonsertib) (Gilead)、GS444217 (Gilead)或GS459679 (Gilead)。Apoptotic signal-regulated kinase 1 (ASK-1) is an essential component of the MAP kinase signaling pathway. ASK-1 activates downstream c-Jun N-terminal kinase (JNK) and p38 MAP kinase, which induce inflammatory cytokine production and apoptosis. In liver diseases such as NAFLD, JNK induces TGF-[beta]-mediated apoptosis of hepatocytes through activation of ASK-1. Thus, blocking, inhibiting, reducing or inhibiting ASK-1 provides a method of treating or preventing liver disease in a subject in need thereof. In some embodiments, an FXR agonist (e.g.,
於一些實施例中，該ASK-1拮抗劑為司隆色替(Gilead；5-(4-環丙基-1H-咪唑-1-基)-2-氟-N-[6-(4-異丙基-4H-1,2,4-***-3-基)-2-吡啶基]-4-甲基苯甲醯胺)。於一些實施例中，司隆色替以2、6或18 mg每天一次之劑量經口投與。 與 LOXL2 拮抗劑組合 In some embodiments, the ASK-1 antagonist is silocetide (Gilead; 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-[6-(4- isopropyl-4H-1,2,4-triazol-3-yl)-2-pyridyl]-4-methylbenzamide). In some embodiments, sloxetine is administered orally at a dose of 2, 6, or 18 mg once daily. In combination with LOXL2 antagonists
離胺醯氧化酶同源物2 (LOXL2)為經由膠原與彈性蛋白纖維之交聯促進纖維化之細胞外基質酶。LOXL2增強膠原於某些組織中之累積及沉積。LOXL2於正常肝組織中不顯著表現，然而，於纖維化肝病中發現LOXL2之增加之表現程度。LOXL2於肝細胞中之上調促進肝損傷及導致肝纖維化。因此，阻斷、抑制、減少或抑制LOXL2提供一種治療或預防有需要個體之肝病之方法。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及LOXL2拮抗劑。Lysamine oxidase homolog 2 (LOXL2) is an extracellular matrix enzyme that promotes fibrosis through the cross-linking of collagen and elastin fibers. LOXL2 enhances collagen accumulation and deposition in certain tissues. LOXL2 is not significantly expressed in normal liver tissue, however, an increased degree of expression of LOXL2 is found in fibrotic liver disease. Upregulation of LOXL2 in hepatocytes promotes liver injury and leads to liver fibrosis. Thus, blocking, inhibiting, reducing or inhibiting LOXL2 provides a method of treating or preventing liver disease in a subject in need thereof. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a LOXL2 antagonist.
於一些實施例中，該LOXL2拮抗劑為抗體。於一些實施例中，FXR促效劑與西妥珠單抗(simtuzumab) (Gilead)組合向有需要個體投與。於一些實施例中，西妥珠單抗以約2 mg/kg至約15 mg/kg哺乳動物體重之劑量投與。於一些實施例中，西妥珠單抗以約75 mg至125 mg之劑量每週一次經皮下投與。In some embodiments, the LOXL2 antagonist is an antibody. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with simtuzumab (Gilead). In some embodiments, cetuzumab is administered at a dose of about 2 mg/kg to about 15 mg/kg of mammalian body weight. In some embodiments, cetuzumab is administered subcutaneously once a week at a dose of about 75 mg to 125 mg.
於一些實施例中，FXR促效劑與PAT-1251 (Pharmakea)組合向有需要個體投與。於一些實施例中，PAT-1251以約1 mg/kg至約75 mg/kg哺乳動物體重之劑量投與。於一些實施例中，PAT-1251以約100至2000 mg之劑量每日經口投與。於一些實施例中，PAT-1251以約500至1000 mg之劑量每日經口投與。In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with PAT-1251 (Pharmakea). In some embodiments, PAT-1251 is administered at a dose of about 1 mg/kg to about 75 mg/kg of mammalian body weight. In some embodiments, PAT-1251 is administered orally daily at a dose of about 100 to 2000 mg. In some embodiments, PAT-1251 is administered orally daily at a dose of about 500 to 1000 mg.
於一些實施例中，FXR促效劑與PXS-5382 (Pharmaxis)組合向有需要個體投與。除了離胺醯氧化酶同源物2 (LOXL2)外，PXS-5382亦展示離胺醯氧化酶同源物3 (LOXL3)。於一些實施例中，PXS-5382以約0.1 mg/kg至約75 mg/kg哺乳動物體重之劑量投與。於一些實施例中，PXS-5382以約25至200 mg之劑量每日經口投與。於一些實施例中，PXS-5382以約50至100 mg之劑量每日經口投與。 與 TGF-β 拮抗劑組合 In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with PXS-5382 (Pharmaxis). In addition to lysine oxidase homolog 2 (LOXL2), PXS-5382 also displays lysine oxidase homolog 3 (LOXL3). In some embodiments, PXS-5382 is administered at a dose of about 0.1 mg/kg to about 75 mg/kg of mammalian body weight. In some embodiments, PXS-5382 is administered orally daily at a dose of about 25 to 200 mg. In some embodiments, PXS-5382 is administered orally daily at a dose of about 50 to 100 mg. In combination with TGF-beta antagonists
轉化生長因子-β (TGF-β)為多功能細胞激素，其於組織修復及傷口癒合中起著重要作用。TGF-β於所有組織中發現及一般而言，TGF-β刺激細胞外基質蛋白之產生以及抑制此等蛋白質之降解。針對維持組織穩態需要此等功能之平衡。TGF-β之抗發炎性及免疫抑制效應之破壞導致肝中許多疾病過程。TGF-β促進慢性肝病之所有疾病階段，從初始肝損傷至發炎及纖維化至肝硬化及肝細胞癌。需要TGF-β用於肝纖維形成發生；TGF-β信號傳導之減弱會減少肝纖維化。因此，阻斷、抑制、減少或抑制TGF-β提供一種治療或預防有需要個體之肝病之方法。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及TGF-β拮抗劑。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及TGF-β拮抗劑。Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that plays an important role in tissue repair and wound healing. TGF-beta is found in all tissues and in general, TGF-beta stimulates the production of extracellular matrix proteins and inhibits the degradation of these proteins. A balance of these functions is required for maintaining tissue homeostasis. Disruption of the anti-inflammatory and immunosuppressive effects of TGF-beta leads to many disease processes in the liver. TGF-beta promotes all disease stages of chronic liver disease, from initial liver injury to inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. TGF-beta is required for liver fibrogenesis; attenuation of TGF-beta signaling reduces liver fibrosis. Thus, blocking, inhibiting, reducing or inhibiting TGF-beta provides a method of treating or preventing liver disease in a subject in need thereof. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a TGF-beta antagonist. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a TGF-beta antagonist.
於一些實施例中，該TGF-β拮抗劑為吡非尼酮。於一些實施例中，該TGF-β拮抗劑為5-甲基-1-苯基吡啶-2(1H)-酮。於一些實施例中，FXR促效劑與吡非尼酮組合向有需要個體投與。於一些實施例中，FXR促效劑與5-甲基-1-苯基吡啶-2(1H)-酮組合向有需要個體投與。於一些實施例中，吡非尼酮以約250 mg至約2500 mg/天之劑量經口投與。於一些實施例中，吡非尼酮以膠囊之形式經口投與。於一些實施例中，吡非尼酮在治療之第一週期間以約267 mg/膠囊每天三個膠囊之劑量隨食物經口投與。於一些實施例中，吡非尼酮在治療之第二週期間以約267 mg/膠囊每天兩個膠囊三次以提供總計約1602 mg/天之劑量隨食物經口投與。於一些實施例中，吡非尼酮於治療之前15天後以約267 mg/膠囊每天三個膠囊三次以提供總計2403 mg/天之劑量隨食物經口投與。 與代謝治療劑組合 In some embodiments, the TGF-beta antagonist is pirfenidone. In some embodiments, the TGF-beta antagonist is 5-methyl-1-phenylpyridin-2(1H)-one. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with pirfenidone. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with 5-methyl-1-phenylpyridin-2(1H)-one. In some embodiments, pirfenidone is administered orally at a dose of about 250 mg to about 2500 mg/day. In some embodiments, pirfenidone is administered orally in capsule form. In some embodiments, pirfenidone is administered orally with food at a dose of about 267 mg/capsule three capsules per day during the first week of treatment. In some embodiments, pirfenidone is administered orally with food during the second week of treatment at about 267 mg/capsule two capsules three times per day to provide a total dose of about 1602 mg/day. In some embodiments, pirfenidone is administered orally with food after 15 days prior to treatment at about 267 mg/capsule three capsules three times per day to provide a total of 2403 mg/day. In combination with metabolic therapeutics
於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及附加代謝治療劑。於一些實施例中，治療或預防有需要個體之纖維化肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及附加代謝治療劑。於一些實施例中，治療或預防有需要個體之代謝性肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及附加代謝治療劑。 與 PPAR δ 促效劑組合 In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and an additional metabolic therapeutic agent. In some embodiments, a method of treating or preventing fibrotic liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and an additional metabolic therapeutic agent. In some embodiments, a method of treating or preventing metabolic liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and an additional metabolic therapeutic agent. In combination with PPAR delta agonists
過氧物酶體增殖物活化受體δ (PPAR δ)為涉及各種慢性病(諸如糖尿病、肥胖、動脈粥樣硬化及癌症)之細胞核激素受體。具體而言，PPAR δ為脂肪酸代謝路徑、葡萄糖代謝及脂肪細胞增殖、分化及細胞凋亡之重要調節劑。PPAR δ促效劑調節葡萄糖代謝、脂肪酸代謝及減輕胰島素抗性。PPAR δ促效劑抑制肝細胞內之脂質沉積物之形成且抑制肝脂肪變性之發展。因此，活化或增加PPAR δ提供一種治療或預防有需要個體之肝病之方法。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及PPAR δ促效劑。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及PPAR δ促效劑。 Peroxisome proliferator-activated receptor delta (PPAR delta) is a nuclear hormone receptor involved in various chronic diseases such as diabetes, obesity, atherosclerosis and cancer. Specifically, PPAR delta is an important regulator of fatty acid metabolic pathways, glucose metabolism, and adipocyte proliferation, differentiation, and apoptosis. PPAR delta agonists regulate glucose metabolism, fatty acid metabolism and reduce insulin resistance. PPAR delta agonists inhibit the formation of lipid deposits within hepatocytes and inhibit the development of hepatic steatosis. Thus, activating or increasing PPAR delta provides a method of treating or preventing liver disease in a subject in need thereof. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a PPAR delta agonist. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a PPAR delta agonist.
於一些實施例中，PPAR δ促效劑為KD-3010 (Kalypsys)。於一些實施例中，FXR促效劑與KD-3010組合向有需要個體投與。於一些實施例中，KD-3010以約5 mg至約200 mg/天之劑量經口投與。於一些實施例中，KD-3010以膠囊之形式經口投與。於一些實施例中，KD-3010以約10 mg每天一次、約20 mg每天一次、約30 mg每天一次、約40 mg每天一次、約60 mg每天一次、或約80 mg每天一次之劑量經口投與。 In some embodiments, the PPAR delta agonist is KD-3010 (Kalypsys). In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with KD-3010. In some embodiments, KD-3010 is administered orally at a dose of about 5 mg to about 200 mg/day. In some embodiments, KD-3010 is administered orally in capsule form. In some embodiments, KD-3010 is administered orally at a dose of about 10 mg once daily, about 20 mg once daily, about 30 mg once daily, about 40 mg once daily, about 60 mg once daily, or about 80 mg once daily vote.
於一些實施例中，該PPAR δ促效劑為KD-3020 (Kalypsys)。 與 PPAR α 促效劑或 PPAR δ/PPAR α 促效劑組合 In some embodiments, the PPAR delta agonist is KD-3020 (Kalypsys). and PPARα agonist or PPARδ/PPARα agonist combination
PPAR α，亦稱作NR1C1 (細胞核受體1 C組成員1)為肝中脂質代謝之主要調節劑。PPAR α在能量剝奪條件期間活化及一旦活化，PPAR α促進脂肪酸之吸收及分解代謝。PPAR α表現隨著高脂肪攝入減少。PPAR α促效劑藉由增加粒線體-β氧化及減少脂肪生成來減少肝脂肪變性。PPAR α促效劑之投與亦導致體重損失。因此，活化或增加PPAR α提供一種治療或預防有需要個體之肝病之方法。於一些實施例中，治療有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及PPAR α促效劑。於一些實施例中，治療有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及PPAR δ促效劑。於一些實施例中，治療有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及雙重PPAR δ/PPAR α促效劑。 PPAR alpha, also known as NR1C1 (
於一些實施例中，該PPAR α促效劑為貝特(fibrate)。於一些實施例中，該PPAR α促效劑為非諾貝特(fenofibrate)。於一些實施例中，FXR促效劑與貝特組合向有需要個體投與。於一些實施例中，FXR促效劑與非諾貝特組合向有需要個體投與。於一些實施例中，非諾貝特以約40 mg至約200 mg/天之劑量經口投與。於一些實施例中，非諾貝特以膠囊之形式經口投與。於一些實施例中，非諾貝特以約150 mg每天一次之劑量經口投與。於一些實施例中，非諾貝特以約120 mg每天一次之劑量經口投與。 In some embodiments, the PPAR alpha agonist is fibrate. In some embodiments, the PPAR alpha agonist is fenofibrate. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with fibrate. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with fenofibrate. In some embodiments, fenofibrate is administered orally at a dose of about 40 mg to about 200 mg/day. In some embodiments, fenofibrate is administered orally in capsule form. In some embodiments, fenofibrate is administered orally at a dose of about 150 mg once daily. In some embodiments, fenofibrate is administered orally at a dose of about 120 mg once daily.
於一些實施例中，該PPAR α促效劑為營養素。於一些實施例中，該PPAR α促效劑為魚油。於一些實施例中，FXR促效劑與魚油組合向有需要個體投與。於一些實施例中，魚油包括α-亞油酸、二十碳五烯酸(EPA)、及二十二碳六烯酸(DHA)。於一些實施例中，魚油以約100 mg至約5,000 mg/天之劑量經口投與。於一些實施例中，魚油以膠囊之形式經口投與。於一些實施例中，魚油以約2,000 mg每天一次之劑量經口投與。於一些實施例中，魚油以約4,000 mg每天一次之劑量經口投與。 In some embodiments, the PPAR alpha agonist is a nutrient. In some embodiments, the PPAR alpha agonist is fish oil. In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with fish oil. In some embodiments, the fish oil includes alpha-linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In some embodiments, the fish oil is administered orally at a dose of about 100 mg to about 5,000 mg/day. In some embodiments, the fish oil is administered orally in capsule form. In some embodiments, the fish oil is administered orally at a dose of about 2,000 mg once daily. In some embodiments, the fish oil is administered orally at a dose of about 4,000 mg once daily.
於一些實施例中，該PPAR δ/PPAR α雙重促效劑為艾拉菲布拉諾(elafibranor) (Genfit)。於一些實施例中，FXR促效劑與艾拉菲布拉諾組合向有需要個體投與。於一些實施例中，艾拉菲布拉諾以約70 mg至約130 mg/天之劑量經口投與。於一些實施例中，艾拉菲布拉諾以膠囊之形式經口投與。於一些實施例中，艾拉菲布拉諾以約80 mg每天一次或約120 mg每天一次之劑量經口投與。與鈉 - 葡萄糖轉運蛋白 1 (SGLT1) 之抑制劑組合 In some embodiments, the PPAR delta/PPAR alpha dual agonist is elafibranor (Genfit). In some embodiments, the FXR agonist is administered to an individual in need thereof in combination with alafibrano. In some embodiments, alafibrano is administered orally at a dose of about 70 mg to about 130 mg/day. In some embodiments, Elafibrano is administered orally in capsule form. In some embodiments, alafibrano is administered orally at a dose of about 80 mg once daily or about 120 mg once daily. In combination with inhibitors of sodium- glucose transporter 1 (SGLT1)
SGLT1為鈉葡萄糖共轉運蛋白家族之成員。SGLT1之抑制延遲及減少小腸中之葡萄糖吸收，因此改善飯後血糖控制。SGLT1亦於腎之近側小管中發現，其中其可介導葡萄糖再吸收。SGLT1為低容量高親和力葡萄糖轉運蛋白。因此SGLT1之抑制可於具有腎功能下降之患者中有益，其中SGLT2抑制不太有效。SGLT1 is a member of the sodium-glucose co-transporter family. Inhibition of SGLT1 delays and reduces glucose absorption in the small intestine, thus improving postprandial glycemic control. SGLT1 is also found in the proximal tubule of the kidney, where it mediates glucose reabsorption. SGLT1 is a low-capacity, high-affinity glucose transporter. Thus inhibition of SGLT1 may be beneficial in patients with decreased renal function, where SGLT2 inhibition is less effective.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與SGLT1抑制劑組合投與。與鈉 - 葡萄糖轉運蛋白 2 (SGLT2) 之抑制劑組合 In some embodiments, an FXR agonist (eg,
SGLT2為鈉葡萄糖共轉運蛋白家族之成員及為鈉依賴性葡萄糖轉運蛋白。SGLT2為涉及腎中葡萄糖再吸收之主要轉運蛋白。SGLT2之抑制可幫助降低由腎再吸收回血液之葡萄糖之量。SGLT2 is a member of the sodium-glucose co-transporter family and is a sodium-dependent glucose transporter. SGLT2 is a major transporter involved in glucose reabsorption in the kidney. Inhibition of SGLT2 can help reduce the amount of glucose reabsorbed back into the blood by the kidneys.
SGLT2抑制劑已證明於患有2型糖尿病(T2DM)與確立之心血管疾病之患者中之心血管及腎保護。越來越多證據表明SGLT2抑制劑亦可藉由降低肝脂肪含量保護肝。SGLT2 inhibitors have demonstrated cardiovascular and renal protection in patients with
於一些實施例中，該SGLT2抑制劑為卡格列淨(canagliflozin)、達格列淨(dapagliflozin)、恩格列淨(empagliflozin)、魯格列淨(luseogliflozin)、伊格列淨(ipragliflozin)、托格列淨(tofogliflozin)、埃格列淨(ertugliflozin)、伊格列淨、瑞格列淨(remogliflozin)或依碳酸瑞格列淨。In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, luseogliflozin, ipragliflozin , tofogliflozin, ertugliflozin, ilagliflozin, remogliflozin or etabonate.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與SGLT2抑制劑組合投與。於一些實施例中，該SGLT2抑制劑為恩格列淨。於一些實施例中，恩格列淨以約10至25 mg每天一次之劑量經口投與。於一些實施例中，恩格列淨以10 mg每天一次之劑量經口投與。於一些實施例中，恩格列淨以25 mg每天一次之劑量經口投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與恩格列淨及利格列汀(linagliptin)組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與恩格列淨及甲福明組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，該SGLT2抑制劑為卡格列淨。於一些實施例中，卡格列淨以約100至300 mg每天一次之劑量經口投與。於一些實施例中，卡格列淨以100 mg每天一次之劑量經口投與。於一些實施例中，卡格列淨以300 mg每天一次之劑量經口投與。In some embodiments, the SGLT2 inhibitor is canagliflozin. In some embodiments, canagliflozin is administered orally at a dose of about 100 to 300 mg once daily. In some embodiments, canagliflozin is administered orally at a dose of 100 mg once daily. In some embodiments, canagliflozin is administered orally at a dose of 300 mg once daily.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與卡格列淨及甲福明組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，該SGLT2抑制劑為達格列淨。於一些實施例中，達格列淨以約5至10 mg每天一次之劑量經口投與。於一些實施例中，達格列淨以5 mg每天一次之劑量經口投與。於一些實施例中，達格列淨以10 mg每天一次之劑量經口投與。In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, dapagliflozin is administered orally at a dose of about 5 to 10 mg once daily. In some embodiments, dapagliflozin is administered orally at a dose of 5 mg once daily. In some embodiments, dapagliflozin is administered orally at a dose of 10 mg once daily.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與達格列淨及甲福明組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與達格列淨及沙格列汀(saxagliptin)組合投與。In some embodiments, an FXR agonist (eg,
另一SGLT2抑制劑為埃格列淨。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與埃格列淨組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與埃格列淨及甲福明組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與埃格列淨及西格列汀(sitagliptin)組合投與。 與 SGLT1 及 SGLT2 二者之雙重抑制劑組合 Another SGLT2 inhibitor is ipagliflozin. In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與抑制腎鈉-葡萄糖共轉運蛋白2及腸SGLT1二者之劑組合投與，其延遲葡萄糖吸收及因此減少飯後葡萄糖。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與抑制腎鈉-葡萄糖共轉運蛋白2及腎SGLT1二者之劑組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與抑制腎SGLT1、腎SGLT2及腸腎SGLT1二者之劑組合投與。In some embodiments, an FXR agonist (e.g.,
SGLT1及SGLT2二者之抑制劑之實例包括(但不限於)索格列淨及利格列淨(licogliflozin)。Examples of inhibitors of both SGLT1 and SGLT2 include, but are not limited to, sopagliflozin and licogliflozin.
於一些實施例中，該雙重SGLT1/2抑制劑為索格列淨。於一些實施例中，索格列淨以約200至約400 mg每天一次之劑量經口投與。於一些實施例中，索格列淨以200 mg每天一次之劑量經口投與。於一些實施例中，索格列淨以400 mg每天一次之劑量經口投與。In some embodiments, the dual SGLT1/2 inhibitor is soxagliflozin. In some embodiments, sopagliflozin is administered orally at a dose of about 200 to about 400 mg once daily. In some embodiments, sopagliflozin is administered orally at a dose of 200 mg once daily. In some embodiments, sopagliflozin is administered orally at a dose of 400 mg once daily.
於一些實施例中，該雙重SGLT1/2抑制劑為利格列淨。於一些實施例中，利格列淨以約2.5至約300 mg之劑量經口投與。於一些實施例中，利格列淨以約30 mg之劑量經口投與。於一些實施例中，利格列淨以約300 mg之劑量經口投與。與乙醯基 -CoA 羧酶 (ACC) 之抑制劑組合 In some embodiments, the dual SGLT1/2 inhibitor is linagliflozin. In some embodiments, linagliflozin is administered orally at a dose of about 2.5 to about 300 mg. In some embodiments, linagliflozin is administered orally at a dose of about 30 mg. In some embodiments, linagliflozin is administered orally at a dose of about 300 mg. In combination with inhibitors of acetyl-CoA carboxylase (ACC)
乙醯基-CoA羧酶(ACC)為生物素依賴性酶，其催化乙醯基-CoA之可逆羧化以產生丙二醯基-CoA。ACC催化再次脂肪生成(DNL)中之速率限制步驟。增加之DNL促進NASH之發病。ACC抑制改善脂肪變性、肝發炎及肝纖維化。Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the reversible carboxylation of acetyl-CoA to produce malonyl-CoA. ACC catalyzes the rate-limiting step in re-lipogenesis (DNL). Increased DNL promotes the pathogenesis of NASH. ACC inhibition ameliorates steatosis, liver inflammation and liver fibrosis.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與ACC抑制劑組合投與。於一些實施例中，該ACC抑制劑為GS-0976。於一些實施例中，GS-0976以約5至20 mg每天一次之劑量經口投與。於一些實施例中，GS-0976以5 mg每天一次之劑量經口投與。於一些實施例中，GS-0976以20 mg每天一次之劑量經口投與。與 GLP1 促效劑組合 In some embodiments, an FXR agonist (eg,
據信肝及脂肪組織二者中之胰島素抗性(IR)為NASH之發病之關鍵驅動因素。患有NASH之個體具有嚴重脂肪IR、伴隨增加之肝IR及重新脂肪生成(DNL)。此等共同促進肝中之過量脂質累積及非酯化脂肪酸(NEFA)之溢出及來自脂肪組織脂肪分解之甘油三酯源之毒性代謝物之釋放，形成NASH之發病中之主要脂毒性損傷。除了驅動固有肝IR及發炎外，認為肝脂毒性進一步促進循環促發炎環境及NASH之IR狀態，其繼而促進惡化脂肪功能障礙及脂肪分解之循環。Insulin resistance (IR) in both liver and adipose tissue is believed to be a key driver in the pathogenesis of NASH. Individuals with NASH have severe adipose IR with concomitant increased hepatic IR and de novo lipogenesis (DNL). These together promote excess lipid accumulation in the liver and spillover of non-esterified fatty acids (NEFAs) and release of toxic metabolites from triglyceride sources from adipose tissue lipolysis, forming the major lipotoxic lesions in the pathogenesis of NASH. In addition to driving intrinsic hepatic IR and inflammation, hepatic lipotoxicity is believed to further promote a circulating pro-inflammatory milieu and the IR state of NASH, which in turn promotes a cycle that worsens lipodystrophy and lipolysis.
已顯示類升糖素胜肽-1 (GLP-1)促效劑改善血糖控制、促進體重損失、改善胰島素敏感性、提高肝酶及減少肝葡萄糖產生。已觀察到於GLP-1療法後之肝脂肪變性之改善，於一些情況下其伴隨氧化壓力及纖維化之減少。Glucagon-like peptide-1 (GLP-1) agonists have been shown to improve glycemic control, promote weight loss, improve insulin sensitivity, increase liver enzymes, and reduce hepatic glucose production. Improvements in hepatic steatosis following GLP-1 therapy have been observed, accompanied in some cases by reductions in oxidative stress and fibrosis.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與GLP1促效劑組合投與。於一些實施例中，該GLP1促效劑為維克托紮(Victoza) (利拉魯肽(liraglutide)；Novo)、司馬魯肽(Semaglutide)、艾塞那肽(exenatide) (AstraZeneca)、杜拉魯肽(dulaglutide) (Eli Lilly)、利西那肽(lixisenatide) (Sanofi)或阿比魯肽(albiglutide) (GSK)。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與GLP1促效劑組合投與。於一些實施例中，該GLP1促效劑為維克托紮。於一些實施例中，維克托紮以約0.5至5 mg每天一次之劑量藉由注射投與。於一些實施例中，維克托紮以約1至3 mg每天一次之劑量藉由注射投與。於一些實施例中，維克托紮以0.6 mg每天一次之劑量藉由注射投與。於一些實施例中，維克托紮以1.2 mg每天一次之劑量藉由注射投與。於一些實施例中，維克托紮以1.8 mg每天一次之劑量藉由注射投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與GLP1促效劑組合投與。於一些實施例中，該GLP1促效劑為司馬魯肽。於一些實施例中，司馬魯肽以0.25 mg每週一次之劑量藉由注射投與。於一些實施例中，司馬魯肽以0.5 mg每週一次之劑量藉由注射投與。與 DGAT 抑制劑組合 In some embodiments, an FXR agonist (eg,
NASH特徵在於肝中之過量甘油三酯(TG)合併發炎及細胞損傷。二醯基甘油醯基轉移酶(DGAT)催化自二醯基甘油及Acyl-CoA之TG合成之最終步驟。認為藉由DGAT催化之反應為甘油三酯合成中之最終及唯一關鍵步驟及對腸吸收(即，DGAT1)及脂肪組織形成(即，DGAT2)係基本的。存在具有不同蛋白質序列及潛在不同生理功能之兩種同功異型物，DGAT1及DGAT2。NASH is characterized by excess triglycerides (TG) in the liver combined with inflammation and cellular damage. Diacylglycerolyltransferase (DGAT) catalyzes the final step of TG synthesis from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is believed to be the final and only critical step in triglyceride synthesis and essential for intestinal absorption (ie, DGAT1) and adipose tissue formation (ie, DGAT2). There are two isoforms, DGAT1 and DGAT2, with different protein sequences and potentially different physiological functions.
飲食甘油三酯不可於胃腸道中直接吸收及於腸中藉由胰脂肪酶分解成游離脂肪酸及單甘油。一旦吸收，游離脂肪酸及甘油在吸收部位(稱作腸上皮細胞)處重新組裝成甘油三酯，及包裝成乳糜微粒以於淋巴系統中輸送以在整個身體中使用。DGAT-1為催化自單醯基甘油或二醯基甘油及脂肪酸之甘油三酯生物合成之步驟之兩種酶中之一者，及主要於腸、肝及脂肪組織中分佈。Dietary triglycerides are not directly absorbed in the gastrointestinal tract and are broken down in the intestine by pancreatic lipase into free fatty acids and monoglycerides. Once absorbed, free fatty acids and glycerol are reassembled into triglycerides at the site of absorption (called enterocytes) and packaged into chylomicrons for transport in the lymphatic system for use throughout the body. DGAT-1 is one of two enzymes that catalyze the steps of triglyceride biosynthesis from mono- or diacylglycerol and fatty acids, and is mainly distributed in the intestine, liver and adipose tissue.
已顯示該酶之抑制於動物模型及臨床試驗中減少脂肪儲存，其導致體重減少。Inhibition of this enzyme has been shown to reduce fat storage in animal models and clinical trials, which results in weight loss.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與DGAT1抑制劑或DGAT2抑制劑組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與DGAT1抑制劑組合投與。於一些實施例中，該DGAT1抑制劑為GSK3008356。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與DGAT2抑制劑組合投與。於一些實施例中，該DGAT2抑制劑為PF-0685571。 與膽汁酸路徑調節劑組合 In some embodiments, the FXR agonist (eg,
膽汁酸與結腸中之受體結合，該等受體促進腸激素(諸如類升糖素胜肽1 (GLP1))之釋放。於肝中，膽汁酸與以負反饋環路調節膽汁酸自膽固醇產生之其他受體結合。在正常情況下，膽汁酸與此等受體結合及抑制新膽汁酸之合成。隨著膽汁酸含量降低，肝必須自膽固醇產生所需膽汁酸，其要求增加之膽固醇攝取及肝中之膽固醇之所產生之減少。肝中之膽固醇累積之減少會降低肝病(諸如但不限於NASH及NAFLD)之肝損傷。Bile acids bind to receptors in the colon that promote the release of gut hormones such as glucagon-like peptide 1 (GLP1). In the liver, bile acids bind to other receptors that regulate the production of bile acids from cholesterol in a negative feedback loop. Under normal conditions, bile acids bind to these receptors and inhibit the synthesis of new bile acids. As bile acid levels decrease, the liver must produce the required bile acids from cholesterol, which requires increased cholesterol uptake and a reduction in the production of cholesterol in the liver. Reduction of cholesterol accumulation in the liver reduces liver damage in liver diseases such as, but not limited to, NASH and NAFLD.
於完成消化後，膽汁酸於小腸之遠側部分(稱作回腸末端)中藉由回腸膽汁酸轉運蛋白(IBAT；亦稱作ASBT或頂端鈉-膽汁酸轉運蛋白)回收。IBAT啟動膽汁酸之轉運，該等膽汁酸於稱作腸肝循環之過程中通過門靜脈流回肝。After digestion is complete, bile acids are recovered by the ileal bile acid transporter (IBAT; also known as ASBT or apical sodium-bile acid transporter) in the distal portion of the small intestine (called the terminal ileum). IBAT initiates the transport of bile acids that flow back to the liver through the portal vein in a process known as the enterohepatic cycle.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與IBAT抑制劑組合投與。於一些實施例中，該IBAT抑制劑為伏裡西巴特(volixibat) (亦稱作SHP626)、馬拉裡西巴特(maralixibat) (Shire)、埃洛比西巴特(elobixibat) (Albireo)或A4350 (Albireo)。於一些實施例中，該IBAT抑制劑為伏裡西巴特。與纖維母細胞生長因子受體調節劑組合 In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與纖維母細胞生長因子(FGF) 19受體或纖維母細胞生長因子(FGF) 21受體之調節劑組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與FGF-19變異體或FGF-21變異體組合投與。In some embodiments, modulation of an FXR agonist (eg,
人類激素FGF-19為肝中膽汁酸合成之主要調節劑及涉及體重維持之代謝過程(包括葡萄糖穩態及甘油三酯調節)中之關鍵信號分子。FGF-19結合至FGF-19受體，從而導致肝脂肪含量減少、肝脂肪變性、發炎及纖維化改善及藉由靶向非酒精性脂肪性肝炎(NASH)之多重發病路徑來改善肝功能。The human hormone FGF-19 is a master regulator of bile acid synthesis in the liver and a key signaling molecule in metabolic processes involved in body weight maintenance, including glucose homeostasis and triglyceride regulation. FGF-19 binds to the FGF-19 receptor, resulting in reduced hepatic fat content, improvement in hepatic steatosis, inflammation and fibrosis, and improved liver function by targeting the multiple pathogenic pathways of nonalcoholic steatohepatitis (NASH).
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與人類FGF-19之變異體組合投與。於一些實施例中，該人類FGF-19之變異體為人類激素FGF-19之經工程改造之變異體。於一些實施例中，該人類FGF-19之變異體為NGM282 (NGM/Merck)。In some embodiments, an FXR agonist (eg,
纖維母細胞生長因子21 (FGF-21)為於許多組織(包括肝)中表現之代謝之關鍵調節劑。許多不同代謝活性組織表現FGF-21，但是大多數激素藉由肝產生。FGF-21之含量藉由代謝壓力源，諸如肥胖、缺少身體鍛煉及代謝性疾病(諸如2型糖尿病)調節。其中發現升高之循環FGF-21含量之病狀包括肥胖、2型糖尿病、心血管疾病、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。此等升高可表示對保護身體免於不良代謝病狀之補償反應。Fibroblast growth factor 21 (FGF-21) is a key regulator of metabolism expressed in many tissues, including the liver. Many different metabolically active tissues express FGF-21, but most hormones are produced by the liver. The levels of FGF-21 are regulated by metabolic stressors such as obesity, physical inactivity, and metabolic diseases such as
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與人類FGF-21之變異體組合投與。於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與PEG化纖維母細胞生長因子(FGF) 21組合投與。於一些實施例中，該PEG化纖維母細胞生長因子(FGF) 21為BMS-986036 (Bristol-Myers-Squibb)。與甲狀腺激素 β 促效劑組合 In some embodiments, an FXR agonist (eg,
脂質代謝之甲狀腺激素影響調節寬範圍之相關健康參數，自血液中之膽固醇及甘油三酯含量至脂肪於肝中之病理積聚。於一些實施例中，肝中之選擇性甲狀腺激素受體β(THR-β)活化改善脂質代謝之失調，導致肝脂肪減少，降低多種動脈粥樣硬化脂質(包括LDL-膽固醇及甘油三酯)及解決NASH。Thyroid hormone effects on lipid metabolism regulate a wide range of relevant health parameters, from cholesterol and triglyceride levels in the blood to the pathological accumulation of fat in the liver. In some embodiments, selective thyroid hormone receptor beta (THR-beta) activation in the liver ameliorates dysregulation of lipid metabolism, resulting in a reduction in hepatic fat and lowering of various atherosclerotic lipids including LDL-cholesterol and triglycerides and resolve NASH.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與甲狀腺激素β促效劑組合投與。於一些實施例中，該甲狀腺激素β促效劑為MGL-3196 (Madrigal Pharmaceuticals)、MGL-3745 (Madrigal Pharmaceuticals)或VK2809 (Viking Therapeutics)。In some embodiments, an FXR agonist (eg,
於一些實施例中，該甲狀腺激素β促效劑為MGL-3196。於一些實施例中，MGL-3196以約50 mg每天一次或約100 mg每天一次，或約200 mg每天一次之劑量經口投與。 於一些實施例中，該甲狀腺激素β促效劑為VK2809。於一些實施例中，VK2809以約5 mg每天一次或約10 mg每天一次，或約20 mg每天一次之劑量經口投與。 其他組合 In some embodiments, the thyroid hormone beta agonist is MGL-3196. In some embodiments, MGL-3196 is administered orally at a dose of about 50 mg once daily, or about 100 mg once daily, or about 200 mg once daily. In some embodiments, the thyroid hormone beta agonist is VK2809. In some embodiments, VK2809 is administered orally at a dose of about 5 mg once daily, or about 10 mg once daily, or about 20 mg once daily. other combinations
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與葡萄糖降低劑、胰島素分泌刺激劑、胰島素增敏劑、脂質降低劑、增加交感神經系統活性之化合物、二十碳五烯酸乙酯、奧貝膽酸或TGR5促效劑組合投與。 In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與以下組合投與：司汀、胰島素增敏藥物、胰島素促分泌素、α-葡萄糖苷酶抑制劑、GLP促效劑、DPP-4抑制劑(諸如西格列汀、維格列汀(vildagliptin)、沙格列汀、利格列汀、安格列汀(anagliptin)、替格列汀(teneligliptin)、阿格列汀(alogliptin)、吉格列汀(gemigliptin)或杜格列汀(dutogliptin))、兒茶酚胺(諸如腎上腺素、去甲腎上腺素或多巴胺(dopamine))、過氧化物酶體增殖物活化受體(PPAR)-γ促效劑(例如，噻唑啶二酮(TZD) [諸如吡格列酮(pioglitazone)、羅格列酮(rosiglitazone)、瑞格列酮(rivoglitazone)或曲格列酮(troglitazone)]、阿格列紮(aleglitazar)、法格列紮(farglitazar)、穆格列紮(muraglitazar)或替格列紮(tesaglitazar))或其組合。於一些情況下，司汀為HMG-CoA還原酶抑制劑。於其他實例中，附加治療劑包括魚油、貝特、維生素(諸如菸酸)、視黃酸(例如，9順式-視黃酸)、菸醯胺核糖核苷或其類似物，或其組合。於一些實例中，促進NAD+
產生之菸醯胺核糖核苷或其類似物(許多酶促反應之受質)包括p450，其為FXR之標靶(例如，參見Yang等人，J. Med. Chem.
50:6458-61, 2007)。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑與諸如司汀、胰島素增敏藥物、胰島素促分泌素、α-葡萄糖苷酶抑制劑、GLP促效劑、DPP-4抑制劑(諸如西格列汀、維格列汀、沙格列汀、利格列汀、安格列汀、替格列汀、阿格列汀、吉格列汀或杜格列汀)、兒茶酚胺(諸如腎上腺素、去甲腎上腺素或多巴胺)、過氧化物酶體增殖物活化受體(PPAR)-γ促效劑(例如，噻唑啶二酮(TZD) [諸如吡格列酮、羅格列酮、瑞格列酮或曲格列酮]、阿格列紮、法格列紮、穆格列紮或替格列紮)或其組合之附加治療劑組合投與，用於治療糖尿病或糖尿病相關病症或病狀。於一些實施例中，FXR促效劑與諸如魚油、貝特、維生素(諸如菸酸)、視黃酸(例如，9順式-視黃酸)、菸醯胺核糖核苷或其類似物，或其組合之附加治療劑組合投與，用於治療糖尿病或糖尿病相關病症或病狀。In some embodiments, the FXR agonist is combined with drugs such as statins, insulin sensitizers, insulin secretagogues, alpha-glucosidase inhibitors, GLP agonists, DPP-4 inhibitors such as sitagliptin, Vildagliptin, saxagliptin, linagliptin, anlogliptin, ticagliptin, alogliptin, gemagliptin, or dougliptin), catecholamines (such as epinephrine, norepinephrine) hormone or dopamine), peroxisome proliferator-activated receptor (PPAR)-gamma agonists (eg, thiazolidinediones (TZDs) [such as pioglitazone, rosiglitazone, rosiglitazone, or troglitazone] ketone], agriza, faglieza, muglieza, or ticaglieza), or a combination thereof, is administered in combination with an additional therapeutic agent for the treatment of diabetes or a diabetes-related disorder or condition. In some embodiments, the FXR agonist is combined with, for example, fish oil, fibrate, vitamins (such as niacin), retinoic acid (eg, 9cis-retinoic acid), nicotinamide riboside, or analogs thereof, Additional therapeutic agents, or combinations thereof, are administered in combination for the treatment of diabetes or a diabetes-related disorder or condition.
於一些實施例中，FXR促效劑與諸如HMG-CoA還原酶抑制劑、魚油、貝特、菸酸或其組合之司汀組合投與用於治療血脂異常。In some embodiments, the FXR agonist is administered in combination with a statine such as an HMG-CoA reductase inhibitor, fish oil, fibrate, niacin, or a combination thereof for the treatment of dyslipidemia.
於另外實施例中，FXR促效劑與諸如視黃酸之維生素組合投與用於治療糖尿病及糖尿病相關病症或病狀，諸如降低升高之體重及/或降低來自食物攝取之升高之血糖。In additional embodiments, FXR agonists are administered in combination with vitamins such as retinoic acid for the treatment of diabetes and diabetes-related disorders or conditions, such as reducing elevated body weight and/or reducing elevated blood sugar from food intake .
於一些實施例中，該法尼醇X受體促效劑與至少一種附加療法投與。於一些實施例中，該至少一種附加療法為降糖劑。於一些實施例中，該至少一種附加療法為抗肥胖劑。於一些實施例中，該至少一種附加療法係選自過氧化物酶體增殖物活化受體(PPAR)促效劑(γ、雙重或泛)、二肽基肽酶(IV)抑制劑、類升糖素胜肽-1 (GLP-I)類似物、胰島素或胰島素類似物、胰島素促分泌素、鈉葡萄糖共轉運蛋白2 (SGLT2)抑制劑、糖噬菌體、人類胰島澱粉樣多肽類似物、雙胍、α-葡萄糖苷酶抑制劑、美格替尼(meglitinide)、噻唑啶二酮及磺脲。於一些實施例中，該至少一種附加療法為甲福明、西格列汀、沙格列汀、瑞格列奈(repaglinide)、那格列奈(nateglinide)、艾塞那肽、利拉魯肽、賴脯胰島素、天門冬胰島素、甘精胰島素、地特胰島素(insulin detemir)、異丙酚胰島素及類胰島血糖素肽1或其任何組合。於一些實施例中，該至少一種附加療法為降脂質劑。於某些實施例中，該至少一種附加療法與法尼醇X受體促效劑同時投與。於某些實施例中，該至少一種附加療法較法尼醇X受體促效劑不頻繁投與。於某些實施例中，該至少一種附加療法較法尼醇X受體促效劑更頻繁投與。於某些實施例中，該至少一種附加療法在投與法尼醇X受體促效劑之前投與。於某些實施例中，該至少一種附加療法於投與法尼醇X受體促效劑之後投與。 與肥胖外科手術組合 In some embodiments, the farnesoid X receptor agonist is administered with at least one additional therapy. In some embodiments, the at least one additional therapy is a hypoglycemic agent. In some embodiments, the at least one additional therapy is an anti-obesity agent. In some embodiments, the at least one additional therapy is selected from peroxisome proliferator-activated receptor (PPAR) agonists (gamma, dual or pan), dipeptidyl peptidase (IV) inhibitors, Glucagon peptide-1 (GLP-I) analogs, insulin or insulin analogs, insulin secretagogues, sodium glucose cotransporter 2 (SGLT2) inhibitors, glycophages, human amylin analogs, biguanides , alpha-glucosidase inhibitors, meglitinide, thiazolidinediones and sulfonylureas. In some embodiments, the at least one additional therapy is metformin, sitagliptin, saxagliptin, repaglinide, nateglinide, exenatide, liralu Peptide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin propofol, and insulin-
NAFLD及NASH之目前最佳治療包括體重減少與生活方式改變、利用或不利用藥物及肥胖外科手術之目前選項。肥胖外科手術為嚴重肥胖(體重指數≥ 35 kg/m2 )個體之有效治療選項，及於大多數患者中提供長期質量損失及肥胖相關聯疾病之解決。NASH之消退及/或組織學改善已於肥胖外科手術後記錄在案。Current best treatments for NAFLD and NASH include weight loss and lifestyle changes, current options with or without medication and bariatric surgery. Bariatric surgery is an effective treatment option for severely obese (body mass index ≥ 35 kg/m 2 ) individuals, and provides long-term mass loss and resolution of obesity-related disease in most patients. Regression and/or histological improvement of NASH has been documented after bariatric surgery.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與肥胖外科手術組合投與。In some embodiments, an FXR agonist (eg,
肥胖外科手術技術可使用腹腔鏡方法進行。一種技術為可調整胃束帶術(AGB)，其中將可充氣及可調整聚矽氧束帶放置於上腹部周圍，接近胃食管連接部，以創造30-mL近側胃囊。於外科手術後，於門診辦公室中進行一系列逐步調整以收縮束帶孔。Bariatric surgical techniques can be performed using a laparoscopic approach. One technique is adjustable gastric banding (AGB), in which an inflatable and adjustable silicone band is placed around the upper abdomen, near the gastroesophageal junction, to create a 30-mL proximal gastric pouch. After surgery, a series of gradual adjustments are performed in the outpatient office to retract the cuff holes.
肥胖外科手術之另一技術為Roux-en-Y胃旁路術(RYGB)。此為近側胃旁路。小的30-至50-mL近側胃囊藉由使用吻合器將其與較大胃部分開來創造。然後使用各種等效腹腔鏡吻合技術以Roux-en-Y方式將胃囊連接至近側空腸。Another technique for bariatric surgery is Roux-en-Y gastric bypass (RYGB). This is the proximal gastric bypass. A small 30- to 50-mL proximal gastric pouch is created by separating it from the larger gastric portion using a stapler. The gastric pouch was then attached to the proximal jejunum in a Roux-en-Y fashion using various equivalent laparoscopic anastomosis techniques.
另一技術為袖狀胃切除術(SG)，其中將胃竇、胃體及胃底之左側部分與中間部分分離。將「較大過量胃」自腹腔移除，留下較小左側彎曲狹窄胃，保留幽門及與十二指腸之通常連接。Another technique is sleeve gastrectomy (SG), in which the left and middle portions of the antrum, corpus and fundus are separated. The "large excess stomach" was removed from the abdominal cavity, leaving a smaller left-sided curved narrow stomach, preserving the pylorus and its usual connection to the duodenum.
仍另一技術為不具有十二指腸轉位之膽胰轉流術(BPD)或具有十二指腸轉位之膽胰轉流術(BPD-DS)。利用此技術，創造部分胃切除術(BPD)或袖狀胃切除術(BPD-DS)，及將小腸分成相似長度之兩部分(消化及膽胰分支)。將消化分支連接至十二指腸(BPD-DS)或胃(BPD)之第一部分。將膽胰分支吻合至遠側小腸。Yet another technique is biliopancreatic diversion without duodenal transposition (BPD) or biliopancreatic diversion with duodenal transposition (BPD-DS). Using this technique, a partial gastrectomy (BPD) or sleeve gastrectomy (BPD-DS) is created, and the small intestine is divided into two parts of similar length (digestive and biliopancreatic branches). The digestive branch is attached to the first part of the duodenum (BPD-DS) or stomach (BPD). The biliopancreatic branch was anastomosed to the distal small intestine.
仍另一技術為將胃吻合及胃束帶組合之垂直束帶胃成形術(VBG)，其係不可調整以創造小胃囊。於製作至胃之切口後，將切口側面吻合，於胃中創造孔用於束帶循環通過。在創造之孔上，將胃吻合。Yet another technique is vertical band gastroplasty (VBG), which combines gastric anastomosis and gastric banding, which is not adjustable to create a small gastric pouch. After the incision to the stomach is made, the incision is anastomosed laterally to create a hole in the stomach for the circulation of the band. On the hole of creation, the stomach is anastomosed.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與肥胖外科手術組合投與。於一些實施例中，該肥胖外科手術技術為胃束帶、胃旁路、袖狀胃切除術、不具有或具有十二指腸轉位之膽胰轉流術、或垂直束帶胃成形術。於一些實施例中，該肥胖外科手術技術為可調整胃束帶(AGB)、Roux-en-Y胃旁路(RYGB)、袖狀胃切除術(SG)、不具有十二指腸轉位之膽胰轉流術(BPD)或具有十二指腸轉位之膽胰轉流術(BPD-DS)、或垂直束帶胃成形術(VBG)。In some embodiments, an FXR agonist (eg,
於一些實施例中，肥胖外科手術為限制型手術、呼吸不良型手術或限制型手術及呼吸不良型手術二者之組合。於一些實施例中，限制型肥胖外科手術包括(但不限於)垂直束帶胃成形術、可調整胃束帶、袖狀胃切除術、胃內氣球(胃氣球)或胃皺紋。於一些實施例中，呼吸不良型肥胖外科手術包括(但不限於)膽胰轉流術、空腸回腸旁路或腔內套管。於一些實施例中，呼吸不良型及限制型肥胖外科手術二者之組合包括(但不限於)胃旁路手術、具有十二指腸轉位之袖狀胃切除術或可植入胃刺激。與維生素組合 In some embodiments, bariatric surgery is restrictive surgery, dyspnea surgery, or a combination of both restrictive and dyspnea surgery. In some embodiments, restrictive bariatric surgery procedures include, but are not limited to, vertical band gastroplasty, adjustable gastric banding, sleeve gastrectomy, intragastric balloon (gastric balloon), or gastric wrinkle. In some embodiments, dyspnea bariatric surgery includes, but is not limited to, biliopancreatic diversion, jejunoileal bypass, or endoluminal cannulation. In some embodiments, a combination of both dyspnea and restrictive bariatric surgery includes, but is not limited to, gastric bypass surgery, sleeve gastrectomy with duodenal transposition, or implantable gastric stimulation. Combine with vitamins
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與維生素組合投與。於一些實施例中，該維生素非經腸或經腸投與。於一些實施例中，該維生素為生育酚、α-生育酚、維生素E、γ-生育酚、生育三烯酚、β-生育酚或δ-生育酚。與細菌組合 In some embodiments, an FXR agonist (eg,
已顯示微生物產品促進肝脂肪變性及發炎之發展或維持，其顯著促進NASH及NAFLD之發展。微生物組受促進發炎及肝脂肪變性之發展之許多因素影響。出於若干原因認為腸道菌群於NASH之發病機制中起作用。首先，已知腸道菌群對營養素之消化及吸收具有大的影響。第二，腸道菌群參與宿主之整體免疫之發展及穩態。因此，某些菌群影響肝發炎之發展。腸道菌群與宿主免疫系統之間之聯繫包括(但不限於)類鐸受體(TLR)及短鏈脂肪酸。於一些實施例中，先天免疫系統影響代謝症候群及肥胖。第三，腸道菌群影響腸道激素(諸如類升糖素胜肽1)之產生，及隨後，對宿主之整體代謝具有影響。肝作為細菌及微生物組分以及存在於門靜脈血中之其他內源及外源毒素之第一接觸點出現(及對其產生初始免疫反應)。鑑於肝以影響整個有機體之形式調節代謝，通過膽汁及腸肝循環將許多物質分佈至腸道，及調節許多激素及免疫反應之能力，可快速瞭解肝影響腸道功能之潛力。腸道、飲食與肝之間之相互作用自然為雙向；激素、發炎性介體及消化及吸收產物均明確影響肝功能。Microbial products have been shown to promote the development or maintenance of hepatic steatosis and inflammation, which significantly contribute to the development of NASH and NAFLD. The microbiome is influenced by many factors that promote the development of inflammation and hepatic steatosis. The gut microbiota is believed to play a role in the pathogenesis of NASH for several reasons. First, it is known that the intestinal flora has a great influence on the digestion and absorption of nutrients. Second, the gut microbiota is involved in the development and homeostasis of the host's overall immunity. Therefore, certain flora influence the development of liver inflammation. Links between the gut microbiota and the host immune system include, but are not limited to, tor-like receptors (TLRs) and short chain fatty acids. In some embodiments, the innate immune system affects metabolic syndrome and obesity. Third, the gut microbiota influences the production of gut hormones such as glucagon-
於一些實施例中，微生物組受促進發炎及肝脂肪變性之發展之許多因素影響；此等因素之非限制性實例包括短鏈脂肪酸(SCFA)及脂多糖(LPS)。 In some embodiments, the microbiome is influenced by a number of factors that promote the development of inflammation and hepatic steatosis; non-limiting examples of such factors include short chain fatty acids (SCFA) and lipopolysaccharides (LPS).
改變之腸道菌群引起肥胖；此關係歸因於短鏈脂肪酸(SCFA)。肥胖個體之腸道中之SCFA之量與健康個體之腸道中之SCFA含量相比升高。肥胖個體具有增加之腸道細菌含量，具有更大能力收集能量(例如，擬桿菌(Bacteroidete)/厚壁菌(Firmicute)比率)；換言之，此等細菌能產生更高量之SCFA。改變之腸道菌群及脂肪肝病最近已相關聯。已顯示SFCA通過不同機制影響肝：改變之腸道菌群導致更大卡路里攝取及升高之SCFA增強腸營養吸收。兩種機制促進肥胖發展，其與肝病相關。酒精增加由腸道菌群之產生為另一機制，藉由該機制改變之腸道菌群影響肝。例如，小兒科NASH患者展示較健康對照及非NASH肥胖患者之彼等之升高之血清酒精濃度。藉由腸道菌群產生之酒精藉由與酒精性脂肪性肝炎之彼等相似機制來促進NASH之發展。Altered gut microbiota causes obesity; this relationship is attributed to short chain fatty acids (SCFA). The amount of SCFAs in the guts of obese individuals is elevated compared to the levels of SCFAs in the guts of healthy individuals. Obese individuals have an increased gut bacterial content with a greater ability to harvest energy (eg, the Bacteroidete/Firmicute ratio); in other words, these bacteria produce higher amounts of SCFA. Altered gut microbiota and fatty liver disease have recently been linked. SFCAs have been shown to affect the liver through different mechanisms: altered gut flora leading to greater calorie intake and elevated SCFAs enhancing intestinal nutrient absorption. Two mechanisms promote the development of obesity, which is associated with liver disease. Increased production of alcohol by gut microbiota is another mechanism by which altered gut microbiota affects the liver. For example, pediatric NASH patients exhibit elevated serum alcohol concentrations compared to their healthy controls and non-NASH obese patients. Alcohol produced by gut flora promotes the development of NASH by mechanisms similar to those in alcoholic steatohepatitis.
改變之腸道菌群與NAFLD及NASH相關聯之又一機制係通過升高之微生物細胞組分，諸如脂多糖(LPS) (即，內毒素)，其於革蘭氏陰性菌中發現。NASH患者於其腸道菌群中具有增加之革蘭氏陰性菌含量。NAFLD及NASH患者亦展示升高之血清內毒素含量。此外，活體內鼠科研究已顯示導致代謝症候群之升高之血清LPS含量。Yet another mechanism by which altered gut microbiota is associated with NAFLD and NASH is through elevated microbial cellular components, such as lipopolysaccharides (LPS) (ie, endotoxins), which are found in Gram-negative bacteria. NASH patients have increased levels of Gram-negative bacteria in their gut flora. Patients with NAFLD and NASH also exhibit elevated serum endotoxin levels. In addition, in vivo murine studies have shown elevated serum LPS levels leading to metabolic syndrome.
於一些實施例中，與本文中所述之FXR促效劑組合投與之附加治療劑為益生菌。於一些實施例中，該益生菌具有抗纖維化、代謝或抗發炎效應。於一些實施例中，該益生菌改變脂質代謝。於一些實施例中，治療或預防有需要個體之肝病之方法包括向該個體投與法尼醇X受體(FXR)促效劑及益生菌。於一些實施例中，該益生菌為微生物、孢子、病毒、噬菌體或其任何組合。於一些實施例中，該益生菌包括鏈球菌(Streptococcus )、雙歧桿菌(Bifidobacterium )、乳酸菌(Lactobacillus )或其任何組合。於一些實施例中，該益生菌減少個體中之酒精產生。於一些實施例中，該益生菌減少酒精脫氫酶活性。於一些實施例中，該益生菌減少LPS之產生。於一些實施例中，該益生菌減少腸道中革蘭氏陰性菌之存在。於一些實施例中，該益生菌調節SCFA之產生。於一些實施例中，該益生菌減少SCFA之產生。 適用於胃腸疾病或病狀之組合 In some embodiments, the additional therapeutic agent administered in combination with an FXR agonist described herein is a probiotic. In some embodiments, the probiotic has anti-fibrotic, metabolic or anti-inflammatory effects. In some embodiments, the probiotic alters lipid metabolism. In some embodiments, a method of treating or preventing liver disease in an individual in need thereof comprises administering to the individual a farnesoid X receptor (FXR) agonist and a probiotic. In some embodiments, the probiotics are microorganisms, spores, viruses, bacteriophages, or any combination thereof. In some embodiments, the probiotic comprises Streptococcus (Streptococcus ), Bifidobacterium (Bifidobacterium ), lactic acid bacteria (Lactobacillus ) or any combination thereof. In some embodiments, the probiotic reduces alcohol production in the individual. In some embodiments, the probiotic reduces alcohol dehydrogenase activity. In some embodiments, the probiotic reduces LPS production. In some embodiments, the probiotic reduces the presence of Gram-negative bacteria in the gut. In some embodiments, the probiotic modulates SCFA production. In some embodiments, the probiotic reduces SCFA production. For combinations of gastrointestinal diseases or conditions
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與抗發炎劑、單株抗體或其組合組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與5-胺基水楊酸劑、皮質類固醇、免疫調節劑、TNF α抑制劑、整合素抑制劑、內皮黏著分子(MAdCAM)抑制劑、JAK激酶抑制劑、IL-12/23抑制劑或S1P1選擇性促效劑組合投與。In some embodiments, an FXR agonist (eg,
5-胺基水楊酸劑包括(但不限於)柳氮磺胺吡啶、美沙拉明(mesalamine)及奧沙拉嗪(olsalazine)。5-Aminosalicylic acid agents include, but are not limited to, sulfasalazine, mesalamine, and olsalazine.
皮質類固醇包括(但不限於)潑尼松(prednisone)、布***(budesonide)、潑尼松龍(prednisolone)及甲基潑尼松龍(methylprednisolone)。Corticosteroids include, but are not limited to, prednisone, budesonide, prednisolone, and methylprednisolone.
免疫調節劑包括(但不限於)咪唑硫嘌呤、6-巰基嘌呤及環孢黴素。Immunomodulators include, but are not limited to, azathioprine, 6-mercaptopurine, and cyclosporine.
TNF α抑制劑包括(但不限於)阿達木單抗(adalimumab)、英夫利昔單抗(infliximab)及戈利木單抗(golimumab)。TNFα inhibitors include, but are not limited to, adalimumab, infliximab, and golimumab.
整合素抑制劑包括(但不限於)那他珠單抗(natalizumab)、維多珠單抗(vedolizumab)及伊曲利珠單抗(etrolizumab)。Integrin inhibitors include, but are not limited to, natalizumab, vedolizumab, and etrolizumab.
內皮黏著分子(MAdCAM)抑制劑包括(但不限於) PF-00547659。Endothelial adhesion molecule (MAdCAM) inhibitors include, but are not limited to, PF-00547659.
JAK激酶抑制劑包括(但不限於)托法替尼(tofacitinib)、巴瑞替尼(baricitinib)、菲戈替尼(filgotinib)及烏帕替尼(upadacitinib)。JAK kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, and upadacitinib.
IL-12/23抑制劑包括(但不限於)尤特克單抗(ustekinumab)。IL-12/23 inhibitors include, but are not limited to, ustekinumab.
S1P1選擇性促效劑包括(但不限於)奧紮莫德(ozanimod)及依曲莫德(etrasimod)。與 JAK 激酶抑制劑組合 S1P1 selective agonists include, but are not limited to, ozanimod and etrasimod. In combination with JAK kinase inhibitors
詹納斯激酶(JAK)為細胞內非受體酪胺酸激酶家族，其經由JAK-STAT路徑轉導細胞激素介導之信號。JAK激酶之抑制可對患有潰瘍性結腸炎之患者具有有益效應。Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signaling via the JAK-STAT pathway. Inhibition of JAK kinases may have beneficial effects in patients with ulcerative colitis.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與JAK激酶抑制劑組合投與。於一些實施例中，該JAK激酶抑制劑為托法替尼。於一些實施例中，托法替尼以約10 mg每天兩次持續8週，之後接著5 mg經口每天兩次之劑量經口投與。於一些實施例中，托法替尼以約10 mg每天兩次之劑量經口投與。與介白素 12 及介白素 23 拮抗劑組合 In some embodiments, an FXR agonist (eg,
介白素12 (IL-12)為由樹突狀細胞、巨噬細胞、嗜中性白血球、及人類類B-淋巴母細胞對抗原刺激自然產生之介白素。IL-12涉及原生T細胞分化成Th1細胞及亦於自然殺手細胞及T淋巴細胞之活化中起作用。IL-23為促發炎細胞激素。已顯示IL-23為Th17維持及擴增之關鍵細胞激素。期望介白素IL-12及IL-23之抑制劑通過抑制某些細胞激素干擾身體之發炎反應之觸發及因此調節某些T細胞之活化。可期望介白素12及介白素23拮抗劑對患有克羅恩氏病之患者有益。可期望介白素12及介白素23拮抗劑對患有活性潰瘍性結腸炎之患者有益。Interleukin 12 (IL-12) is an interleukin naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells in response to antigenic stimulation. IL-12 is involved in the differentiation of naive T cells into Th1 cells and also plays a role in the activation of natural killer cells and T lymphocytes. IL-23 is a pro-inflammatory cytokine. IL-23 has been shown to be a key cytokine for Th17 maintenance and expansion. Inhibitors of the interleukins IL-12 and IL-23 are expected to interfere with the triggering of the body's inflammatory response by inhibiting certain cytokines and thus modulate the activation of certain T cells.
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與介白素12及介白素23拮抗劑組合投與。於一些實施例中，該介白素12及介白素23拮抗劑為優特克單抗。於一些實施例中，優特克單抗以初始約260 mg，接著每8週90 mg之劑量經靜脈內投與。於一些實施例中，優特克單抗以初始約390 mg，接著每8週90 mg之劑量經靜脈內投與。於一些實施例中，優特克單抗以初始約520 mg，接著每8週90 mg之劑量經靜脈內投與。In some embodiments, an FXR agonist (eg,
於一些實例中，FXR促效劑與附加治療劑(諸如抗生素、皮質類固醇、或附加抗發炎或免疫調節療法)組合投與用於治療發炎相關腸病。於一些情況下，FXR促效劑與甲硝噠唑(metronidazole)、萬古黴素(vancomycin)、非達黴素(fidaxomicin)、皮質類固醇或其組合組合投與用於治療發炎相關腸病。於一些實施例中，FXR促效劑與己酮可可鹼(pentoxifylline)、抗發炎劑及血管舒張藥物組合投與。In some examples, the FXR agonist is administered in combination with additional therapeutic agents such as antibiotics, corticosteroids, or additional anti-inflammatory or immunomodulatory therapies for the treatment of inflammation-associated bowel disease. In some instances, the FXR agonist is administered in combination with metronidazole, vancomycin, fidaxomicin, corticosteroids, or a combination thereof for the treatment of inflammation-associated bowel disease. In some embodiments, the FXR agonist is administered in combination with pentoxifylline, an anti-inflammatory agent, and a vasodilator.
發炎有時與假膜性結腸炎相關聯。於一些實例中，假膜性結腸炎係與細菌過度生長(諸如難辨梭狀芽孢桿菌(C. dificile )過度生長)相關聯。於一些實施例中，FXR促效劑與抗生素(諸如甲硝噠唑、萬古黴素、非達黴素或其組合)組合投與用於治療與細菌過度生長相關聯之發炎(例如，假膜性結腸炎)。於一些實施例中，FXR促效劑與索利黴素(solithromycin) (酮內酯抗生素) (Cempra)組合投與。Inflammation is sometimes associated with pseudomembranous colitis. In some instances, pseudomembranous colitis is associated with bacterial overgrowth, such as C. difficile ( C. dificile ) overgrowth. In some embodiments, the FXR agonist is administered in combination with an antibiotic (such as metronidazole, vancomycin, fidaxomycin, or a combination thereof) for the treatment of inflammation (eg, pseudomembrane) associated with bacterial overgrowth. colitis). In some embodiments, the FXR agonist is administered in combination with solithromycin (a ketolide antibiotic) (Cempra).
於一些實施例中，FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)與阿片促效劑、膽汁酸螯合劑、抗膽鹼能劑、三環抗抑鬱劑、5-HT3拮抗劑、混合阿片受體促效劑/拮抗劑、抗菌劑、神經激肽拮抗劑或其組合組合投與。In some embodiments, an FXR agonist (eg,
於一些實施例中，該阿片促效劑為洛哌丁胺(loperamide)。In some embodiments, the opioid agonist is loperamide.
於一些實施例中，該膽汁酸螯合劑為消膽胺(cholestyramine)、考來替泊(colestipol)或考來維侖(colesevelam)。In some embodiments, the bile acid sequestrant is cholestyramine, colestipol, or colesevelam.
於一些實施例中，該抗膽鹼能劑為雙環胺(dicyclomine)。In some embodiments, the anticholinergic agent is dicyclomine.
於一些實施例中，該三環抗抑鬱劑為丙咪嗪、地昔帕明(desipramine)或去甲替林(nortriptyline)。In some embodiments, the tricyclic antidepressant is imipramine, desipramine, or nortriptyline.
於一些實施例中，該5-HT3拮抗劑為阿洛司瓊(alosetron)或雷莫司瓊(ramosetron)。In some embodiments, the 5-HT3 antagonist is alosetron or ramosetron.
於一些實施例中，該混合阿片受體促效劑/拮抗劑為伊盧多啉(eluxadoline)或ORP-101。In some embodiments, the mixed opioid receptor agonist/antagonist is eluxadoline or ORP-101.
於一些實施例中，該抗菌劑為利福昔明(rifaximin)。In some embodiments, the antibacterial agent is rifaximin.
於一些實施例中，該神經激肽拮抗劑為艾波度坦(ibodutant)。In some embodiments, the neurokinin antagonist is ibodutant.
於一些實施例中，與FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)組合投與之組合劑中之任一者以醫藥上可接受之鹽形式投與。 套組及製品In some embodiments, any of the combination agents administered in combination with an FXR agonist (eg,
用於本文中所述之治療應用中，本文中亦描述套組及製品。於一些實施例中，此等套組包含經隔室化以接受一或多個容器(諸如小瓶、管及類似者)之載體、包裝或容器，該(等)容器各包含待用於本文中所述方法中之分開要素中之一者。適宜容器包括(例如)瓶、小瓶、注射器及試管。於一些實施例中，該等容器自各種材料(諸如玻璃或塑膠)形成。Kits and articles of manufacture are also described herein for use in the therapeutic applications described herein. In some embodiments, such kits comprise carriers, packages, or containers that are compartmentalized to receive one or more containers (such as vials, tubes, and the like), each container(s) comprising a container(s) to be used herein. one of the separate elements of the method. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the containers are formed from various materials, such as glass or plastic.
本文中所提供之製品含有包裝材料。醫藥包裝材料之實例包括(但不限於)吸塑包裝、瓶、管、吸入器、泵、袋、小瓶、容器、注射器、瓶、及適用於所選調配物及意欲投與模式及治療之任何包裝材料。考慮將本文中所提供之化合物及組合物之寬範圍之調配物作為用於將自FXR調節受益之本文中所述疾病或病狀中之任一者之各種治療。The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any suitable for the chosen formulation and intended mode of administration and treatment Packaging material. The broad range of formulations of the compounds and compositions provided herein are contemplated as various treatments for any of the diseases or conditions described herein that would benefit from FXR modulation.
此等套組視情況包含化合物與識別描述或與其於本文中所述方法中之用途相關之標籤或說明。Such kits optionally include labels or instructions for the compound associated with the identification description or its use in the methods described herein.
套組通常包含一或多個附加容器，針對本文中所述化合物之用途，各具有自商業及使用者立場所需之各種材料中之一或多者(諸如試劑，視情況以濃縮形式，及/或裝置)。此等材料之非限制性實例包括(但不限於)緩衝劑、稀釋劑、填料、針、注射器；列出含量及/或使用說明之載體、包裝、容器、小瓶及/或管標籤，及具有使用說明之包裝插頁。通常亦包含一組說明。Kits typically contain one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and /or device). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, fillers, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and labels with Package insert with instructions for use. Usually also contains a set of instructions.
於一些實施例中，標籤在容器上或與容器相關聯。於一些情況下，當將形成標籤之字母、數字或其他特徵附接、模壓或蝕刻至容器自身時，標籤在容器上；於一些情況下，當標籤存在於亦固持容器之接受器或載體中(例如，作為包裝插頁)時，該標籤與容器相關聯。於一些情況下，標籤係用於指示待用於特定治療應用之內容物。於一些情況下，標籤指示內容物之使用指導，諸如用於本文中所述方法中。In some embodiments, the label is on or associated with the container. In some cases, the label is on the container when the letters, numbers or other features that form the label are attached, molded or etched to the container itself; in some cases, when the label is present in a receptacle or carrier that also holds the container (eg as a package insert), the label is associated with the container. In some cases, labels are used to indicate the contents to be used for a particular therapeutic application. In some cases, the label indicates directions for use of the contents, such as for use in the methods described herein.
於某些實施例中，包含FXR促效劑(例如，化合物1或其醫藥上可接受之鹽)之醫藥組合物於包裝或分配器裝置中呈現，於一些情況下，其含有一或多個單位劑型。於一些情況下，包裝(例如)含有金屬或塑膠箔，諸如泡殼包裝。於一些情況下，包裝或分配器裝置隨附投與說明。於一些情況下，包裝或分配器亦隨附與容器相關聯之通知，以由調節醫藥之製造、使用或銷售之政府機關規定之形式，該通知反映由針對人類或獸醫投與之藥物形式之機關批准。於一些情況下，此通知(例如)為由美國食品與藥品管理局針對處方藥批准之標籤，或批准之產品插頁。於一些情況下，於相容醫藥載劑中調配之含有本文中所提供之化合物之組合物亦經製備，放入適宜容器中，及標記用於治療指定病狀。 實例In certain embodiments, pharmaceutical compositions comprising an FXR agonist (eg,
下列實例僅出於說明目的提供且不限制本文中所提供之申請專利範圍之範圍。 實例1：NASH活性研究(STZ模型)The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. Example 1: NASH Activity Study (STZ Model)
於雄性C57BL/6中藉由於出生2天後單一皮下注射200 µg STZ，接著於4週齡後隨意飼喂高脂飲食(HFD)來誘導NASH。當繼續HFD時，將本文中所揭示之FXR促效劑之組合給藥4至8週以測定對NASH之效應。整個研究利用手持式血糖計量測空腹血糖。藉由臨床化學分析儀量測血清丙胺酸胺基轉移酶(ALT)、天冬胺酸胺基轉移酶(AST)及甘油三酯(TG)。使用甘油三酯E-測試套組(Wako, Tokyo, Japan)量測肝組織中之TG之含量。在包埋於組織-TEK最佳切削溫度(O.C.T.)化合物中，於液氮中速凍及儲存在-80℃下之組織上進行肝切片之組織學分析。將該等切片切割(5 µm)，空氣乾燥及於丙酮中固定。針對蘇木精及曙紅(H&E)染色，將肝切片藉由布因氏(Bouin’s)溶液預固定及然後用蘇木精及曙紅溶液染色。利用天狼星(Sirius)紅染色評估(區域-3)肝纖維化之程度。 實例2 NASH活性研究(AMLN模型)NASH was induced in male C57BL/6 by a single subcutaneous injection of 200
於雄性C57BL/6小鼠中藉由利用AMLN飲食(DIO-NASH) (D09100301, Research Diet, USA) (40%脂肪(18%反式脂肪)，40%碳水化合物(20%果糖)及2%膽固醇)之飲食誘導來誘導NASH。將動物保持該飲食29週。於飲食誘導26週後，進行肝活組織檢查用於疾病進展(肝脂肪變性及纖維化)之基線組織學評估，分層及根據肝纖維化階段、脂肪變性評分及體重隨機分成治療組。於活組織檢查3週後，將小鼠分成治療組及藉由口服管飼本文中所揭示之FXR促效劑之組合每日給藥持續8週。在研究結束時，藉由檢查各自利用H&E及天狼星紅染色之組織切片進行肝活組織檢查以評估肝脂肪變性及纖維化。藉由比色測定藉由膠原酸解之羥基脯胺酸殘基來量測肝中之總膠原含量。於單一測定中使用自動分析儀Cobas C-111與市售套組(Roche Diagnostics, Germany)根據製造商之說明量測肝勻漿中之甘油三酯及總膽固醇含量。 實例3：肝內膽汁鬱積模型In male C57BL/6 mice by using AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18% trans fat), 40% carbohydrate (20% fructose) and 2% Cholesterol) to induce NASH. Animals were kept on this diet for 29 weeks. After 26 weeks of diet induction, liver biopsies were performed for baseline histological assessment of disease progression (hepatic steatosis and fibrosis), stratified and randomized into treatment groups according to liver fibrosis stage, steatosis score and body weight. After 3 weeks of biopsy, mice were divided into treatment groups and administered by oral gavage a combination of FXR agonists disclosed herein daily for 8 weeks. At the end of the study, liver biopsies were performed to assess hepatic steatosis and fibrosis by examining tissue sections each stained with H&E and Sirius Red. Total collagen content in liver was measured by colorimetric assay of hydroxyproline residues by acid hydrolysis of collagen. Triglyceride and total cholesterol levels in liver homogenates were measured in a single assay using an automated analyzer Cobas C-111 with a commercial kit (Roche Diagnostics, Germany) according to the manufacturer's instructions. Example 3: Intrahepatic Cholestasis Model
於齧齒動物中藉由17a-乙炔基***(EE2)處理誘導之實驗性肝內膽汁鬱積廣泛用於活體內模型以檢查涉及***誘導之膽汁鬱積之機制。肝內膽汁鬱積於成年雄性小鼠中藉由每日皮下注射10mg/kg 17a-乙炔基***(EE2)持續5天來誘導。本文中所揭示之FXR促效劑之組合之測試藉由在膽汁鬱積之EE2誘導期間投與進行。膽汁鬱積效應藉由評估肝/體重比率及量測血清總膽汁酸及鹼性磷酸酶含量來定量，該等含量使用來自Diagnostic Chemicals Ltd.之試劑及對照及Cobas Mira plus CC分析儀(Roche Diagnostics)量測。針對組織學及有絲***量測，將來自各小鼠之肝樣品固定於10%中性緩衝福馬林中。將載玻片使用標準方案利用蘇木精及曙紅染色及用顯微鏡檢查結構變化。藉由針對Ki67之免疫組織化學染色評價肝細胞增殖。 實例4：大鼠ANIT模型Experimental intrahepatic cholestasis induced by 17a-ethinylestradiol (EE2) treatment in rodents is widely used in in vivo models to examine the mechanisms involved in estrogen-induced cholestasis. Intrahepatic cholestasis was induced in adult male mice by daily subcutaneous injection of 10 mg/kg 17a-ethinylestradiol (EE2) for 5 days. Testing of the combinations of FXR agonists disclosed herein was performed by administration during EE2 induction of cholestasis. Cholestatic effect was quantified by assessing liver/body weight ratio and measuring serum total bile acid and alkaline phosphatase levels using reagents and controls from Diagnostic Chemicals Ltd. and Cobas Mira plus CC analyzer (Roche Diagnostics) Measure. Liver samples from each mouse were fixed in 10% neutral buffered formalin for histological and mitotic measurements. Slides were stained with hematoxylin and eosin and examined for structural changes using standard protocols. Hepatocyte proliferation was assessed by immunohistochemical staining for Ki67. Example 4: Rat ANIT Model
於膽汁鬱積之長期治療模型中在0.01至10 mg/kg之劑量範圍下評價本文中所述之FXR促效劑及附加治療劑之組合。此模型係用於評價用於治療諸如以下之膽汁鬱積性肝病之本文中所述之組合療法：膽汁酸吸收不良(例如，原發性或繼發性膽汁酸腹瀉)、膽汁逆流性胃炎、膠原性結腸炎、淋巴細胞性結腸炎、轉移性結腸炎、不明性結腸炎、阿拉吉歐症候群、膽道閉鎖、導管開放性肝移植排斥、骨髓或幹細胞移植相關之移植物抗宿主疾病、囊性纖維化肝病、及腸外營養相關肝病。Combinations of FXR agonists and additional therapeutic agents described herein were evaluated in a long-term treatment model of cholestasis at doses ranging from 0.01 to 10 mg/kg. This model is used to evaluate the combination therapy described herein for the treatment of cholestatic liver diseases such as: bile acid malabsorption (eg, primary or secondary bile acid diarrhea), bile reflux gastritis, collagen Colitis, lymphocytic colitis, metastatic colitis, unexplained colitis, Arajgio syndrome, biliary atresia, duct-open liver transplant rejection, graft-versus-host disease associated with bone marrow or stem cell transplantation, cystic Fibrotic liver disease, and parenteral nutrition-related liver disease.
將大鼠用含α-萘基異硫氰酸酯(ANIT) (0.1% w/w)之食物處理3天，之後用本文中所述化合物以0.01至10 mg/kg之劑量治療(「Veh」)。將非膽汁鬱積對照組飼喂不含ANIT之標準飼料，及用作非膽汁鬱積對照動物(「對照」)。於口服給藥14天後，分析大鼠血清之分析物含量。LLQ，定量下限。平均值± SEM；n = 5。於大鼠血清中量測肝膽管損傷指示劑之含量，諸如升高之循環天冬胺酸胺基轉移酶(AST)、丙胺酸胺基轉移酶(ALT)、膽紅素及膽汁酸之升高之含量。ANIT暴露誘導深膽汁鬱積及肝細胞損傷。改善許多此等指示劑中之許多之本文中所述之FXR促效劑及附加治療劑之組合可用於治療上述疾病或病狀。 實例5：小鼠慢性DSS結腸炎模型Rats were treated with a diet containing alpha-naphthyl isothiocyanate (ANIT) (0.1% w/w) for 3 days before treatment with the compounds described herein at doses ranging from 0.01 to 10 mg/kg ("Veh ”). The non-cholestatic control group was fed standard chow without ANIT and served as non-cholestatic control animals ("Control"). Rat serum was analyzed for
慢性聚葡糖硫酸鈉(DSS)誘導之小鼠模型係用於測試本文中所述之組合療法針對發炎性腸病(IBD)之治療潛能。藉由以下誘導慢性結腸炎：對小鼠飼喂含2% DSS之飲用水5天及普通飲用水5天，然後再重複此飼喂週期兩次，總計三個週期。結腸炎約於DSS飼喂之第一週期後發展，其藉由體重損失、糞便稠度及直腸出血監測。藉由與開始2% DSS水飼喂同時向小鼠投與來測試本文中所述之FXR促效劑及附加治療劑之組合。或者，於2% DSS水及普通水之第一飼喂週期後進行組合療法之測試。在向小鼠投與本文中所述之組合療法之時期期間，藉由對體重、糞便稠度及直腸出血之觀察來監測治療效應。於安樂死後，藉由量測結腸重量及長度，藉由H&E染色關於黏膜發炎及結構變化之結腸組織學，及與疾病相關之基因之蛋白質及RNA表現進一步定量疾病發展及本文中所述之組合療法之效應。 實例6：授受性T-細胞轉移結腸炎小鼠模型A chronic polyglucose sodium sulfate (DSS)-induced mouse model was used to test the therapeutic potential of the combination therapies described herein for inflammatory bowel disease (IBD). Chronic colitis was induced by feeding the mice with 2% DSS in drinking water for 5 days and normal drinking water for 5 days, then repeating this feeding cycle twice for a total of three cycles. Colitis developed approximately after the first cycle of DSS feeding and was monitored by weight loss, stool consistency, and rectal bleeding. Combinations of FXR agonists and additional therapeutic agents described herein were tested by administering to mice at the same time as the initiation of 2% DSS water feeding. Alternatively, the combination therapy was tested after the first feeding cycle of 2% DSS water and normal water. Treatment effects were monitored by observation of body weight, stool consistency, and rectal bleeding during periods in which mice were administered the combination therapy described herein. After euthanasia, disease progression and combinations described herein were further quantified by measuring colon weight and length, colon histology for mucosal inflammation and structural changes by H&E staining, and protein and RNA expression of disease-related genes The effect of therapy. Example 6: Donor-acceptor T-cell transfer colitis mouse model
將授受性T-細胞轉移結腸炎模型接受作為人類發炎性腸病(IBD)之相關小鼠模型。為誘導此模型之結腸炎，將CD4 T-淋巴細胞群體自供體小鼠之脾分離。隨後，將CD4+CD45RB高T-細胞之子群體藉由細胞分選使用流動式細胞測量術純化。將經純化之CD4+CD45RB高T-細胞注射至受血者嚴重聯合免疫缺陷(SCID)小鼠之腹膜腔。於T-細胞轉移約3至6週後結腸炎發展，其藉由體重損失、糞便不一致或血性腹瀉監測。本文中所述之FXR促效劑及附加治療劑之組合之測試與將經純化之CD4+CD45RB高T-細胞注射至受血者SCID小鼠中同時開始。或者，本文中所述之FXR促效劑及附加治療劑之組合於T-細胞轉移2或3週後投與，此時結腸炎已於該模型中發展。在將本文中所述之FXR促效劑及附加治療劑之組合向小鼠投與之時期期間，可藉由對體重、糞便稠度或直腸出血之觀察結果監測治療效應。於安樂死後，藉由量測結腸重量及長度，及藉由H&E染色關於與疾病相關之黏膜發炎及結構變化之結腸組織學及基因之蛋白質及RNA表現進一步定量疾病發展及該等化合物之效應。The recipient T-cell transfer colitis model was adopted as a relevant mouse model of human inflammatory bowel disease (IBD). To induce colitis in this model, a population of CD4 T-lymphocytes was isolated from the spleen of donor mice. Subsequently, a subpopulation of CD4+CD45RB high T-cells was purified by cell sorting using flow cytometry. Purified CD4+CD45RB high T- cells were injected into the peritoneal cavity of blood recipient severe combined immunodeficiency (SCID) mice. Colitis develops approximately 3 to 6 weeks after T-cell transfer, monitored by weight loss, fecal inconsistency, or bloody diarrhea. Testing of the combinations of FXR agonists and additional therapeutic agents described herein was initiated concurrently with the injection of purified CD4+CD45RB high T-cells into recipient SCID mice. Alternatively, the combination of an FXR agonist described herein and an additional therapeutic agent is administered 2 or 3 weeks after T-cell transfer, when colitis has developed in this model. During the period in which the combination of an FXR agonist described herein and an additional therapeutic agent is administered to the mice, the effect of the treatment can be monitored by observation of body weight, stool consistency, or rectal bleeding. After euthanasia, disease progression and the effects of these compounds were further quantified by measuring colon weight and length, and by H&E staining for colon histology and protein and RNA expression of genes associated with disease-related mucosal inflammation and structural changes.
結果：CD4+CD45RBhi
T-細胞轉移導致自基線之12% (p＜0.05)體重減少，其藉由(1R,4R)-4-羥基-N-(((1R,4R)-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(2-甲氧基噻唑-5-基)苯基)環己烷-1-甲酰胺(化合物2) (10 mg/kg)、抗IL-12p40及CsA逆轉。結腸炎之標誌，結腸W/L於媒劑組中相對於不具有T-細胞轉移之對照小鼠增加2.8倍(p＜0.05)。如與媒劑相比，經化合物2治療之小鼠各自顯示在10 mg/kg及30 mg/kg下結腸W/L之41%及38%減少(p＜0.01)。利用抗IL-12/23及CsA治療各自顯示結腸W/L之52%及34%改善。經媒劑處理之小鼠針對發炎、增生及腺體損失之平均組織病理學評分各自為4、3及2，具有很少或無糜爛，及平均組織病理學評分加總為10。10及30 mg/kg之化合物2各自將評分加總顯著降低71% (p＜0.01)及74% (p＜0.01)，與藉由抗IL-12/23之78%降低(p＜0.01)相當。化合物2及抗IL-12/23二者均顯示跨所有組織病理學終點之相似改善。雖然CsA改善結腸W/L，但是其不顯示組織病理學參數之顯著改善。Results: CD4+CD45RB hi T-cell transfer resulted in a 12% (p<0.05) weight loss from baseline by (1R,4R)-4-hydroxy-N-(((1R,4R)-4-( 4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexane-1-carboxamide (compound 2) (10 mg/kg), anti-IL-12p40 and CsA reversal. A marker of colitis, colonic W/L increased 2.8-fold (p<0.05) in the vehicle group relative to control mice without T-cell transfer. Compound 2-treated mice showed a 41% and 38% reduction in colonic W/L at 10 mg/kg and 30 mg/kg, respectively, as compared to vehicle (p<0.01). Treatment with anti-IL-12/23 and CsA showed a 52% and 34% improvement in colon W/L, respectively. Vehicle-treated mice had mean histopathological scores of 4, 3, and 2 for inflammation, hyperplasia, and glandular loss, respectively, with little or no erosion, and mean histopathological scores totaled 10. 10 and 30
化合物2 (非膽汁酸FXR促效劑)有效減少授受性T-細胞轉移模型之結腸炎，具有優於CsA且與抗IL-12/23治療相當之功效。化合物2表示可提供IBD之替代治療之一種新穎類別口服藥劑。 實例7：CCl4
纖維化模型
於BALB/c雄性小鼠中藉由每兩週一次投與藉由腹膜內注射投與之CCl4
來誘導纖維化。將CCl4
於油中以1:1調配及以1 ml/kg IP注射。於纖維化誘導2至4週後，藉由口服管飼每日投與本文中所述之FXR促效劑及附加治療劑之組合持續2至6治療週，同時繼續CCl4
投與。在研究終止時，將肝用福馬林固定及用天狼星紅染色用於纖維化之組織病理學評價。藉由比色測定藉由膠原酸解之羥基脯胺酸殘基來量測總膠原含量。藉由臨床化學分析儀量測血清丙胺酸胺基轉移酶(ALT)及天冬胺酸胺基轉移酶(AST)。實例 8 ：化合物 1 於健康個體中之 PK/PD 及安全性評估 In BALB / c male mice administered once every two weeks by intraperitoneal injection and by administration fibrosis induced with CCl 4. The oil in CCl 4 to 1: 1 and formulated in a 1 ml / kg IP injection. After induction of fibrosis in 2 to 4 weeks, administered by oral gavage daily herein FXR agonist compositions of agents of additional therapeutic agent treatment duration 2-6 weeks, while continuing with CCl 4 and administered. At study termination, livers were formalin-fixed and stained with Sirius Red for histopathological evaluation of fibrosis. Total collagen content was measured by colorimetric assay of hydroxyproline residues by acid hydrolysis of collagen. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by a clinical chemistry analyzer. Example 8 : PK/PD and Safety Assessment of
目的：此研究之目的為評估化合物1之單一及多個口服劑量之安全性及耐受性，表徵化合物1之單一及多重口服劑量之藥物動力學(PK)，表徵化合物1之單一及多個口服劑量之藥效動力學(PD)，及識別化合物1之建議多個口服劑量水平用於患者之將來研究。該研究為健康男性個體中之人類中首次，2部分，單中心，1期，隨機，雙盲，安慰劑對照之研究。Objective: The purpose of this study was to evaluate the safety and tolerability of single and multiple oral doses of
納入標準：具有18.0至30.0 kg/m2 之BMI及大於60 Kg之重量之18至65歲健康男性個體。Inclusion criteria: Healthy male subjects aged 18 to 65 with a BMI of 18.0 to 30.0 kg/m 2 and a weight of greater than 60 Kg.
個體：A部分——56個健康男性個體。B部分——60個健康男性個體。Subjects: Part A - 56 healthy male subjects. Part B - 60 healthy male individuals.
研究藥物：呈口服錠劑投與之化合物1。Study Drug:
安慰劑：與研究藥物相同之口服錠劑，但是不含有化合物1。 變量Placebo: Oral lozenge identical to study drug, but without
安全性：不良事件，臨床實驗室，生命體徵，12-導聯心電圖，身體檢查。Safety: Adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, physical examination.
PK：血漿化合物1濃度，血漿PK參數。PK:
PD：7-α-羥基-4-膽烯-3-酮(C4)之血漿含量、纖維母細胞生長因子19 (FGF-19)之血漿含量及總膽汁酸之含量(僅針對B部分)。研究設計 A 部分 —— 單一遞增劑量 [SAD] PD: Plasma levels of 7-α-hydroxy-4-cholen-3-one (C4), plasma levels of fibroblast growth factor 19 (FGF-19) and levels of total bile acids (for Part B only). A part of the study design - a single ascending dose [SAD]
7組(每組8個健康男性個體)以約20 mg至約400 mg之範圍之各種口服劑量水平(例如，約20 mg、約30 mg、約50 mg、約100 mg、約150 mg、約200 mg及約400 mg劑量)投與化合物1之單一劑量。來自各組之兩個個體被提供安慰劑，及來自各組之其餘6個個體接受化合物1。
B部分——多重遞增劑量[MAD]7 groups (each group of 8 healthy male subjects) at various oral dose levels ranging from about 20 mg to about 400 mg (eg, about 20 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg and approximately 400 mg doses) administered a single dose of
6組(每組10個健康男性個體)各自以研究化合物1之多個口服劑量之安全性、耐受性、PK及PD。所有組之個體在第1至14天每日一次接受化合物1之遞增多重口服劑量或匹配安慰劑。在各給藥日在禁食條件下進行給藥。各組之患者在該研究之第1至14天每日一次接受化合物1之約20 mg、約40 mg、約50 mg、約80 mg、約100 mg及約150 mg之多個口服劑量。各組之八個成員接受化合物1，及各組之兩個成員接受安慰劑。結果 藥物動力學 MAD 部分 The safety, tolerability, PK and PD of multiple oral doses of
於以20 mg至150 mg之範圍每日一次口服給藥投與化合物1之14天後，觀察到血漿藥物暴露隨劑量之增加，如圖1中所示。測定化合物1於給藥後24小時於血漿中具有高含量，指示持續PK譜。藥效動力學 MAD 部分 膽汁酸 After 14 days of oral administration of
圖2顯示在第14天針對安慰劑及約50 mg至約150 mg/天群組之膽汁酸含量之產生的平均變化。接受化合物1之約50 mg至150 mg群組各顯示膽汁酸含量減少。C4 Figure 2 shows the mean change in production of bile acid levels on
圖3A中呈現MAD部分之第14天之絕對C4血漿含量的算術平均值圖。在第14天於約20 mg至約150 mg化合物1之多個劑量後，針對化合物1之最高劑量水平之平均C4含量低於安慰劑治療。C4含量之減少在約50 mg及以上係顯著。平均C4含量在第14天於給藥後24小時保持減少。FGF-19 A graph of the arithmetic mean of absolute C4 plasma levels on
於約20 mg至約150 mg化合物1之多個劑量後，平均FGF-19含量增加，如圖3B中所示。平均FGF-19含量之增加最大值在給藥後約6至10小時達到。
實例9：非酒精性脂肪性肝炎(NASH)之臨床試驗Mean FGF-19 levels increased after multiple doses of about 20 mg to about 150 mg of
以下描述人類之非酒精性脂肪性肝炎(NASH)臨床試驗之非限制性實例。Non-limiting examples of clinical trials of nonalcoholic steatohepatitis (NASH) in humans are described below.
目的：此研究之目的為評價化合物1單藥療法於患有NASH之個體中之安全性及耐受性，表徵化合物1之藥物動力學(PK)，表徵化合物1劑量及反應之藥效動力學(PD)，使用磁共振成像-質子密度脂肪分數(MRI-PDFF)估計化合物1之活性，及NASH纖維化生物標誌物。Objectives: The purpose of this study was to evaluate the safety and tolerability of
研究設計：此為患有NASH之個體之兩部分研究，其由(第1部分)約50 mg化合物1持續4週之開放式，未經對照，單中心評估，接著(第2部分)約50 mg至約80 mg研究藥物(化合物1或安慰劑)持續12週之雙盲，安慰劑對照，多中心評估組成。Study Design: This is a two-part study in individuals with NASH consisting of (Part 1) approximately 50 mg of
第1部分：評估約50 mg化合物1治療4週之開放式，未經對照，單中心研究；招募10個個體。Part 1: An open-label, uncontrolled, single-center study evaluating approximately 50 mg of
第2部分：約50 mg至約80 mg化合物1治療持續12週之雙盲，安慰劑對照，多中心評估；約55個個體將以2:1比率隨機分成化合物1或安慰劑組。將前31個個體隨機分成約80 mg化合物1或安慰劑組。將剩餘24個個體隨機分成約50 mg化合物1或安慰劑組。在該研究期間針對個別個體不允許劑量調整。Part 2: About 50 mg to about 80
納入標準：(1) 18至75歲男性及女性個體；(2)基於活組織檢查或成像診斷為NASH；(3)在篩選期間藉由MRI-PDFF量測之肝脂肪含量≥10%；(4)在研究藥物之第一劑量之前之30天(或5個藥物消除半衰期)內無研究藥劑；(5)服用GLP1促效劑、SGLT-2抑制劑或可允許他汀之個體必須以穩定劑量在研究藥物之第一劑量之前至少三個月；(6)個體可服用＜ 800 IU/天之劑量之維生素E，條件為該劑量在研究藥物之第一劑量之前為穩定劑量持續至少3個月。Inclusion criteria: (1) Male and female individuals aged 18 to 75; (2) NASH diagnosed based on biopsy or imaging; (3) Liver fat content ≥10% as measured by MRI-PDFF during screening; ( 4) No study drug within 30 days (or 5 drug elimination half-lives) before the first dose of the study drug; (5) Individuals taking GLP1 agonists, SGLT-2 inhibitors or permissible statins must take a stable dose At least three months prior to the first dose of study drug; (6) Subjects may take vitamin E at doses < 800 IU/day, provided that dose is a stable dose for at least 3 months prior to the first dose of study drug .
排除標準：(1)任何其他肝病(例如，酒精性肝病、病毒性肝炎等)之歷史或存在或肝移植史；(2)任何肝活組織檢查時存在肝硬化(4期纖維化)；(3)過量消耗酒精；(4)在篩選之前之6個月內體重損失＞ 10%或在篩選期間＞ 5%；(5)合併用藥，該等藥物為強或中度CYP3A4抑制劑，或具有窄治療指數之CYP3A4物質。功效評估：藉由MRI-PDFF及NASH生物標誌物量測之肝脂肪含量%。安全性評估：安全性評估將包括收集不良事件、生命體徵及身體檢查，12-導聯ECG，實驗室評估及伴隨治療之驗證。若臨床指定，則可更頻繁進行實驗室測試及程序。Exclusion criteria: (1) History or presence of any other liver disease (eg, alcoholic liver disease, viral hepatitis, etc.) or history of liver transplantation; (2) Presence of cirrhosis (
藥物動力學評估：根據PK取樣時程表採取血液樣品。PK參數(Cmax 、tma x、t½、Ctrough 、CLss/F、Cavg(0-24 h) 、AUC0-tau 、AUC0-t 、AUC0-inf )將藉由非室分析估計。Pharmacokinetic Assessment: Blood samples were taken according to the PK sampling schedule. PK parameters (C max, t ma x, t½, C trough, CLss / F, C avg (0-24 h), AUC 0-tau, AUC 0-t, AUC 0-inf) The estimated by non-compartmental analysis .
藥效動力學(PD)評估：根據PD (C4、FGF-19、膽汁酸)取樣時程表採取血液樣品。Pharmacodynamic (PD) assessment: Blood samples were taken according to the PD (C4, FGF-19, bile acids) sampling schedule.
生物標誌物評估：藉由以下量測纖維化：源自量測透明質酸、III型前膠原胺基端肽(PIIINP)、金屬蛋白酶1之組織抑制劑(TIMP-1)評分作為纖維化之生物標誌物之增強之肝纖維化(ELF)；III型膠原之前肽(Pro-C3)作為纖維化之生物標誌物； NAFLD纖維化評分(NFS)以識別晚期纖維化(年齡、高血糖、體重指數、血小板計數、白蛋白及AST/ALT比率)； FIB-4評分(年齡、AST、ALT及血小板計數)以對纖維化程度進行分級。Biomarker assessment: Fibrosis was measured by the following measures: Hyaluronic acid, procollagen type III aminotelopeptide (PIIINP), tissue inhibitor of metalloproteinase 1 (TIMP-1) score derived from the measurement of fibrosis Biomarkers Enhanced Liver Fibrosis (ELF); Precollagen Type III (Pro-C3) as a biomarker of fibrosis; NAFLD Fibrosis Score (NFS) to identify advanced fibrosis (age, hyperglycemia, body weight) index, platelet count, albumin and AST/ALT ratio); FIB-4 score (age, AST, ALT and platelet count) to grade the degree of fibrosis.
膽汁酸組成：血清膽汁酸(藉由LC-MS量測之總膽汁酸及15種膽汁酸小組)；特定比率及分析方法。Bile acid composition: Serum bile acids (total bile acids and panel of 15 bile acids measured by LC-MS); specific ratios and analytical methods.
主要終點：不良事件(AE)、嚴重不良事件(SAE)及實驗室異常之發生率、嚴重度及結果。Primary endpoint: incidence, severity and outcome of adverse events (AEs), serious adverse events (SAEs) and laboratory abnormalities.
探索性終點：使用MRI-PDFF藉由肝脂肪定量估計活性。Exploratory endpoint: Activity was estimated by quantification of liver fat using MRI-PDFF.
研究長度：於第1部分中之募集個體參與該研究持續約12週，其包含4週篩選期，4週(28天)治療期及4週隨訪期。於第2部分中募集之個體將參與該研究持續約20週，其包含約4週篩選期，12週(84天)治療期及4週隨訪期。 研究治療(第1部分)：於第1部分中募集之個體接受約50 mg化合物1持續28個連續日。Study Length: Subjects recruited in
研究治療(第2部分)：於第2部分中募集之個體將接受化合物1 (約80 mg或約50 mg)或匹配安慰劑持續84個連續日。結果 —— 研究第 1 部分 Study Treatment (Part 2): Subjects recruited in
於該研究中募集之患有NASH之10個患者每日接受約50 mg劑量之化合物1持續28天之時間，如上所述。在利用化合物1治療之前，於利用化合物1治療28天後，然後於停止利用化合物1治療又28天后，評估各患者之肝脂肪含量。針對各組之肝脂肪自基線之所產生的平均變化示於圖4中，及指示患者顯示於利用化合物1治療28天後脂肪肝沉積自基線平均減少20.3%。Ten patients with NASH enrolled in this study received
在開始治療時，於開始治療14天後，於28天終點時，及於停止治療又28天後量測個體之血清脂質含量。LDL-C、甘油三酯及HDL-C自基線所產生之平均變化各自示於圖5A、圖5B及圖5C中。Individuals' serum lipid levels were measured at initiation of treatment, 14 days after initiation of treatment, at the end of
在投與化合物1之前，於將化合物1給藥14天後，及於將化合物1給藥28天後評估個體中之丙胺酸胺基轉移酶(ALT)及γ-麩胺醯基轉移酶(GGT)之含量。此等生物標誌物自基線所產生之變化%可見於圖6A、圖6B中。ALT顯示在第14天自基線減少7.9%，及在第28天進一步下降至基線以下16.5%。GGT含量在第13天減少23.2%，及在第28天自基線減少36.3%。Individuals were assessed for alanine aminotransferase (ALT) and gamma-glutamyltransferase ( GGT) content. The % change from baseline for these biomarkers can be seen in Figures 6A, 6B. ALT showed a 7.9% reduction from baseline on
圖7顯示來自實例8之健康患者及來自實例9之第1部分之患者二者在治療期間之化合物1之血漿含量。化合物1之血漿含量於利用化合物1給藥後24小時針對NASH及健康患者二者相似。化合物1含量在此24小時時間於健康及NASH患者二者中保持幾乎恆定，表明化合物1具有持續PK譜。 結果——第2部分研究Figure 7 shows the plasma levels of
具有活組織檢查證實之NASH或kPa＞
8.5之瞬時彈性成像發現連同如由MRI-PDFF量測之至少10%之肝脂肪含量的男性及女性有資格參與。已顯示肝脂肪自基線減少30%或更多與NASH患者之組織學改善相關。於接受化合物1之患者中，於各自以50 mg及80 mg劑量之12/16患者(75.0%)及13/14 (92.8%)患者中觀察到肝脂肪自基線減少約30%或更多，如與2/18 (11.1%)經安慰劑治療之患者相比(各自參見圖10及圖11)。此等結果證實對化合物1之劑量反應關係。Men and women with biopsy-proven NASH or transient elastography findings of kPa > 8.5 together with a liver fat content of at least 10% as measured by MRI-PDFF were eligible to participate. A 30% or more reduction in liver fat from baseline has been shown to correlate with histological improvement in NASH patients. In
利用化合物1之肝脂肪減少之量級係足夠穩健，各自利用50 mg及80 mg之化合物1治療之患者之31% (n=5)及29% (n=4)達成其肝中之脂肪之正常含量(定義為平均小於5%)。因為NASH經定義為在過量肝脂肪之情況下之發炎性肝病，肝脂肪之標準化可係有益及可與更長期臨床效益相關。安慰劑組之患者中無一者達成肝脂肪標準化。The magnitude of liver fat reduction with
當將各治療小組作為群組時，利用化合物1肝脂肪自基線減少之平均變化為針對50 mg劑量組為38% (參見圖8)及針對80 mg劑量組為55% (參見圖9)，如與利用安慰劑6%相比，導致各自利用50 mg及80 mg劑量之化合物1之32%及49%之安慰劑校正的肝脂肪改善。此等發現優於藉由開發之其他FXR藥物所報道者及亦與開發之針對NASH之其他藥物標靶有利比較，其亦在給藥之12週利用MRI-PDFF評價肝脂肪變化。When treating groups as cohorts, the mean change from baseline in liver fat reduction with
除了肝脂肪改善，利用化合物1治療亦導致其他NASH生物標誌物改善。應用自基線減少30%以將患者分類為對治療之反應者，化合物1與安慰劑相比顯示對ALT及GGT減少之更高反應率(未顯示數據)。In addition to improvement in liver fat, treatment with
化合物1劑量組二者之患者之子集顯示血清ALT及AST之升高，其中大多數似乎短暫。此等變化係無症狀及與血清膽紅素含量之任何變化不相關。似乎此等升高係臨床不顯著及可能由於肝細胞由於利用化合物1治療快速脫脂之良性適應。 第12週肝脂肪含量(LFC)之事後分析A subset of patients in both the
使用第2部分研究之結果之簡單及多重線性回歸分析探索第12週與基線之間之LFC變化(%)之潛在預測因子，包括基線及第4週之人口統計學、實驗室及LFC值。針對顯著預測因子，用於預測第12週≥30%相對LFC減少之最佳臨限值及性能藉由接受者操作特徵下面積(AUC)分析測定。Potential predictors of LFC change (%) between
如上所指出，在第12週，化合物1顯著降低LFC，其中平均相對減少為55% (80 mg)及38% (50 mg)相對於安慰劑6%。化合物1達成患者之93% (80 mg)及75% (50 mg)之≥30%相對LFC減少相對於安慰劑11%。第4週相對LFC減少(回歸係數：1.243，p＜0.001)及血清鹼性磷酸酶(ALP)增加(回歸係數：-0.294，p=0.032)為第12週LFC減少之顯著預測因子。使用-19.3%作為臨限值，第4週相對LFC變化達成0.975之AUC，89%之敏感性及95%之特異性用於預測≥30%第12週相對LFC減少；針對4週6.9% ALP增加之臨限值，此等量度為0.889、96%及76%。組合模型提供0.962、89%及95%之值，表明ALP之貢獻係假的。參見圖13。As noted above,
於此研究中，第4週之相對LFC減少強烈預測第12週之LFC減少。實例 10 ：大腸激躁症候群之臨床試驗 In this study, the relative LFC reduction at
以下描述人類之大腸激躁症候群臨床試驗之非限制性實例。Non-limiting examples of clinical trials of irritable bowel syndrome in humans are described below.
目的：此研究之目的為表徵化合物1或其醫藥上可接受之鹽於患有腹瀉型大腸激躁症候群(IBS-D)伴膽汁酸吸收不良(BAM)之個體中之安全性、藥效動力學及活性。Objective: The purpose of this study is to characterize the safety and pharmacodynamics of
主要目標：使用Bristol糞便形式量表(BSFS)評價化合物1或其醫藥上可接受之鹽及安慰劑對糞便次數及形式之複合終點之影響。Primary objective: To evaluate the effect of
次要目標：表徵化合物1或其醫藥上可接受之鹽及安慰劑之安全性及耐受性，表徵其對總糞便BA及糞便中之主要BA之比率(鵝去氧膽酸[CDCA]%、膽酸[CA]%)之影響，表徵其對糞便脂肪含量之影響，表徵其對腸功能評分之各分量(例如，腸運動次數、稠度、易於排出、完全排空之感覺)之影響，表徵其對IBS總體症狀評分之影響，表徵其對最嚴重腹痛(WAP)之影響，表徵其對接受營救藥劑之患者比例之影響，表徵其對空腹血清C4及FGF-19含量之影響，表徵其對選定研究位點處之結腸運送時間(在24及48小時之幾何中心)之影響。Secondary objectives: To characterize the safety and tolerability of
納入標準：滿足IBS-D之Rome III標準之18至75歲男性及女性個體。如由下列標準中之一或多者測定之BAM之證據：當前處於膽汁酸螯合劑療法，症狀改善；基於最後60天內之量測，增加之總糞便BA (糞便BA必須＞2337 µmole/48 hr)；在篩選期間至少52 ng/mL之空腹血清C4含量；育齡女性個體必須在篩選期間具有陰性血清妊娠測試，同意在該研究期間不妊娠，及同意在整個研究及於化合物1或其醫藥上可接受之鹽之最後劑量後長達3個月使用節育。有生育小孩潛力之男性個體必須同意在該研究期間及於化合物1或其醫藥上可接受之鹽之最後劑量後長達1個月使用節育(雙屏障法)。Inclusion Criteria: Male and female individuals aged 18 to 75 who met Rome III criteria for IBS-D. Evidence of BAM as measured by one or more of the following criteria: current bile acid sequestrant therapy, improvement in symptoms; increased total fecal BA based on measurements within the last 60 days (fecal BA must be >2337 µmole/48 hr); fasting serum C4 levels of at least 52 ng/mL during screening; female individuals of childbearing age must have a negative serum pregnancy test during screening, agree not to become pregnant during the study, and agree to be pregnant throughout the study and on
排除標準：存在已知引起腹瀉或便秘之任何其他醫療狀況(例如，腸手術、潰瘍性結腸炎、克羅恩氏病、IBS伴便秘等)；腎病(例如，血清肌酸酐為2.5 mg/dL或更大)；肝病(例如，天冬胺酸胺基轉移酶＞2.5 ULN及/或丙胺酸胺基轉移酶＞2.5 ULN)；在篩選之前之30天(或5個藥物消除半衰期)內使用研究用新穎藥物；具有可能預期壽命小於2年之活動嚴重醫療疾病；在篩選之前一年內活性物質濫用或酗酒；妊娠、計畫妊娠、妊娠可能(例如，在該研究期間不願意使用有效節育)或哺乳；任何其他醫療狀況或社會環境，據研究者之見解其將妨礙研究順從或阻止研究之完成。Exclusion Criteria: Presence of any other medical condition known to cause diarrhea or constipation (eg, bowel surgery, ulcerative colitis, Crohn's disease, IBS with constipation, etc.); renal disease (eg, serum creatinine 2.5 mg/dL) or greater); liver disease (eg, aspartate aminotransferase >2.5 ULN and/or alanine aminotransferase >2.5 ULN); use within 30 days (or 5 drug elimination half-lives) prior to screening Novel drug for investigational use; active serious medical condition with probable life expectancy of less than 2 years; active substance abuse or alcoholism within one year prior to screening; pregnancy, planned pregnancy, possible pregnancy (eg, reluctance to use effective birth control during the study period) ) or breastfeeding; any other medical condition or social environment which, in the opinion of the investigator, would prevent study compliance or prevent study completion.
研究處理：各個體在第1至28天將接受研究藥物之單一口服每日劑量(安慰劑或10至300 mg化合物1或其醫藥上可接受之鹽)；安慰劑或化合物1或其醫藥上可接受之鹽應在早上與至少4盎司之水一起服用，每天儘可能接近同樣時間。為最小化食物對化合物1或其醫藥上可接受之鹽之吸收之潛在影響，應在進食之前1小時或於進食後2小時服用。若錯過安慰劑或化合物1或其醫藥上可接受之鹽之早上劑量，則其可在同一天晚點服用(距計畫給藥時間至多12小時)；然而，若完全錯過每日劑量，則其應在第二天補足(其應被記錄為錯過劑量)。Study Treatment: Each subject will receive a single oral daily dose of study drug (placebo or 10 to 300 mg of
營救藥劑：在治療期期間針對定義為一天至少三次糞便伴6或更大之BSFS之未經控制之腹瀉可視需要每日兩次投與洛派丁胺2 mg。Rescue Agents:
功效評估：糞便之次數及形式之複合終點：糞便次數x糞便形式(BSFS 1至7) =複合評分/天；比較自篩選至治療期之給定週(7天)之複合評分。糞便(隨機現場糞便收集)中之總BA及主要BA之比率(% CDCA，% CA)：針對第4週篩選比較糞便中之平均總BA；針對第4週篩選比較糞便中之平均CDCA及CA組合之百分比。糞便脂肪含量(隨機現場糞便收集)。結腸轉運時間：在篩選至第4週針對能進行此分析之現場比較24及48小時之平均幾何中心。腸功能：比較自篩選至治療期之給定週(7天)之日記之各分量(腸運動次數、稠度、易於排出及完全排空之感覺)之總評分。IBS總體症狀評分：個體被問「你如何評估過去7天你的IBS總體症狀？」；自篩選至治療期之各週(7天)比較平均IBS總體症狀評分(0=無，1=輕微，2=中度，3=嚴重，及4=極其嚴重)。最嚴重腹痛(WAP)：每日日記將包含WAP疼痛量表，0=無疼痛及10=可想像之最嚴重疼痛；自篩選至治療期之各週(7天)比較平均每週WAP評分。使用營救藥劑：比較在治療期期間接受營救藥劑之個體之比例。Efficacy assessment: composite endpoint of stool frequency and form: stool frequency x stool form (
生物標誌物：空腹血清C4及FGF-19含量：將進行探索性分析以評價治療與各生物標誌物之含量之間之關係。此外，將探索各生物標誌物與功效終點之間之關係。若可得，則結腸轉運。Biomarkers: Fasting Serum C4 and FGF-19 Levels: Exploratory analyses will be performed to evaluate the relationship between treatment and levels of each biomarker. In addition, the relationship between each biomarker and efficacy endpoints will be explored. Colonic transit if available.
主要終點：自篩選(在隨機分組之前之7天)至第4週使用BSFS之糞便次數及形式之一週平均複合評分。Primary endpoint: Weekly mean composite score of stool frequency and form with BSFS from Screening (7 days prior to randomization) to
次要終點：自篩選(在隨機分組之前之7天)至第1週、第2週及第3週使用BSFS之糞便次數及形式之一週平均複合評分；自篩選(在隨機分組之前之7天)至第1週、第2週、第3週及第4週使用BSFS之糞便次數及形式之一週兩個(2)最高值的平均複合評分；自篩選(在隨機分組之前之7天)至第1週、第2週、第3週及第4週之糞便次數之一週平均複合評分；自篩選(在隨機分組之前之7天)至第1週、第2週、第3週及第4週使用BSFS之糞便形式之一週平均複合評分；自篩選(在隨機分組之前之7天)至第1週、第2週、第3週及第4週之平均每週WAP評分；自篩選(在隨機分組之前之7天)至第1週、第2週、第3週及第4週之平均每週IBS總體症狀評分；自篩選至第4週糞便中之平均總糞便BA及主要BA (鵝去氧膽酸[CDCA]%，膽酸[CA]%)；自篩選至第4週糞便中之平均總糞便脂肪含量；空腹血清C4與FGF-19含量之間之關聯以各評估功效；在篩選及第4週時之平均總結腸轉運時間(在24及48小時之幾何中心)——在選定研究現場處進行。 實例11：潰瘍性結腸炎之臨床試驗Secondary endpoints: Weekly mean composite score of stool frequency and form using BSFS from screening (7 days prior to randomization) to Weeks 1, 2, and 3; self-screening (7 days prior to randomization) ) to Week 1, Week 2, Week 3, and Week 4 Mean composite score of the two (2) highest values for one week of stool frequency and form using BSFS; from screening (7 days prior to randomization) to Weekly mean composite score of stool frequency at Weeks 1, 2, 3, and 4; from Screening (7 days before randomization) to Weeks 1, 2, 3, and 4 Weekly mean composite score using stool form of BSFS; mean weekly WAP scores from screening (7 days prior to randomization) through Weeks 1, 2, 3, and 4; Mean weekly IBS global symptom scores from 7 days before randomization) to Weeks 1, 2, 3, and 4; mean total faecal BA and major BA (goose) in feces from screening to Week 4 Deoxycholic acid [CDCA]%, cholic acid [CA]%); mean total fecal fat content in feces from screening to week 4; association between fasting serum C4 and FGF-19 content to assess efficacy for each; Mean Total Colonic Transit Time at Screening and Week 4 (geometric at 24 and 48 hours) - performed at selected study sites. Example 11: Clinical Trial of Ulcerative Colitis
以下描述人類之潰瘍性結腸炎臨床試驗之非限制性實例。Non-limiting examples of human ulcerative colitis clinical trials are described below.
目的：此研究之目的為表徵化合物1或其醫藥上可接受之鹽於患有中度至嚴重潰瘍性結腸炎之個體中之安全性、藥效動力學及活性。Objective: The objective of this study was to characterize the safety, pharmacodynamics and activity of
主要目標：藉由在第12週比較UC-100評分之平均變化，如與安慰劑相比來評價化合物1或其醫藥上可接受之鹽於UC中之影響。Primary objective: To evaluate the effect of
次要目標：評價3-分量Mayo評分(基於糞便頻率、直腸出血及內視鏡發現，評分範圍0至9)之變化，評價化合物1或其醫藥上可接受之鹽及安慰劑對潰瘍性結腸炎內視鏡嚴重度指數(UCEIS)之影響，評價化合物1或其醫藥上可接受之鹽及安慰劑對Robarts組織學指數(RHI)之影響，評價總Mayo評分之變化，評價Mayo評分之分量(糞便頻率、直腸出血、內視鏡評分)之變化，評估臨床反應(Mayo評分自基線減少30%或更多及3或更多點，連同0或1之直腸出血子評分或1點或更多之直腸出血子評分之減少)，評估臨床緩解(於任何個體中2或更少點之Mayo評分，連同不具有超過一點子評分)，評價組織學指數之變化，評價對營救藥劑之需求，評價對發炎性腸病調查表(IBDQ)之影響，評估糞便鈣衛蛋白含量及血清C-反應性蛋白含量之變化，在第12週化合物1或其醫藥上可接受之鹽與安慰劑之間對空腹血清C4及FGF-19含量之影響。Secondary objectives: To evaluate changes in the 3-component Mayo score (
研究治療：各個體在第1至84天將接受研究藥物(安慰劑或化合物1或其醫藥上可接受之鹽)之單一口服每日劑量。允許合併用藥：若個體在內視鏡篩選之前具有皮質類固醇之穩定劑量(最大值為潑尼松30 mg/天或布***(entocort) 6 mg/天)至少2週，若不存在劑量調整，則可在篩選、治療及隨訪期期間繼續皮質類固醇。若個體在內視鏡篩選之前具有口服胺基水楊酸、咪唑硫嘌呤、6-巰基嘌呤或胺甲喋呤之穩定劑量至少3週，若不存劑量調整，則可在篩選、治療及隨訪期期間繼續該藥劑。禁止藥劑：在第一次給藥之前≥8週，個體必須停止使用抗腫瘤壞死因子(TNF)療法、優特克單抗或維多珠單抗。在內視鏡篩選之前至少8週(即，洗出期)，個體必須停止任何研究藥劑、用於UC之藥劑(除了允許之合併用藥)或影響腸功能之藥劑。此等藥劑亦不可在篩選、治療及隨訪期期間投與以避免混淆資料分析。Study Treatment: Each subject will receive a single oral daily dose of study drug (placebo or
納入標準：在篩選之前至少3個月診斷為UC之18至75歲男性及女性個體。在篩選期間藉由6至12 (包含端值)之Mayo評分(範圍0至12)及至少2之內視鏡評分(範圍0至3)與至少15 cm涉及之組織定義之中度至嚴重活性UC。必須進行內視鏡評分之中心讀取。在第一次給藥(即，基線)之前≥8週，先前已接受抗腫瘤壞死因子(TNF)療法、優特克單抗或維多珠單抗之個體必須中斷療法。目前接受利用下列療法中之至少一者治療或具有對其反應失敗或耐受之歷史：口服5-胺基水楊酸、口服皮質類固醇、胺甲喋呤、6-巰基嘌呤及咪唑硫嘌呤。育齡女性個體必須在篩選期間具有陰性血清妊娠測試，同意在該研究期間不妊娠，及同意在整個研究及於化合物1或其醫藥上可接受之鹽之最後劑量後長達3個月使用節育形式。有生育小孩潛力之男性個體必須同意在該研究期間及於化合物1或其醫藥上可接受之鹽之最後劑量後長達1個月使用節育(雙屏障法)。Inclusion criteria: Male and female individuals aged 18 to 75 years with a diagnosis of UC at least 3 months prior to screening. Moderate to severe activity was defined by a Mayo score of 6 to 12 (
排除標準：診斷為克羅恩氏病或未定型結腸炎或與克羅恩氏病或顯微鏡性結腸炎或放射性結腸炎或缺血性結腸炎一致之瘺管之存在或歷史；在篩選之12週記憶體在可需要手術介入之嚴重廣泛性結腸炎；腸道之證實或疑似感染。一旦感染清除，個體可經再次篩選；腎病(例如，血清肌酸酐為2.5 mg/dL或更大)；肝病(例如，天冬胺酸胺基轉移酶＞2.5 ULN及/或丙胺酸胺基轉移酶＞2.5 ULN)；可具有預期壽命小於2年之活動嚴重醫療疾病；在篩選之前之一年內活性物質濫用或酗酒；妊娠、計畫妊娠、妊娠可能(例如，在研究期間不願意使用有效節育)或哺乳。Exclusion Criteria: Diagnosis of Crohn's disease or indeterminate colitis or presence or history of fistula consistent with Crohn's disease or microscopic colitis or radiation colitis or ischemic colitis; within 12 weeks of screening Memory in severe generalized colitis that may require surgical intervention; confirmed or suspected infection of the bowel. Once infection clears, individuals can be rescreened; renal disease (eg, serum creatinine 2.5 mg/dL or greater); liver disease (eg, aspartate aminotransferase >2.5 ULN and/or alanine aminotransferase) Enzyme >2.5 ULN); may have active serious medical illness with a life expectancy of less than 2 years; active substance abuse or alcoholism within one year prior to screening; pregnancy, planned pregnancy, possible pregnancy (eg, reluctance to use effective during study birth control) or breastfeeding.
功效評估：UC-100評分：基於內視鏡、組織學及糞便頻率之複合評分；潰瘍性結腸炎內視鏡嚴重度指數(UCEIS)：3個領域之內視鏡評分：血管模式(評分1至3)，出血(評分1至4)及糜爛及潰瘍(評分1至4)。將在治療組之間比較自基線至第12週之評分之平均變化。Robarts組織學指數(RHI)：4個區域之組織學評分：慢性發炎性浸潤(評分0至3)，固有層嗜中性白血球(評分0至3)，上皮嗜中性白血球(評分0至3)及糜爛或潰瘍(評分0至3)。將在治療組之間比較自基線至第12週之評分之平均變化。Mayo評分(MS)：總MS (評分1至12) – 4個區域包括糞便頻率(評分0至3)，直腸出血(評分0至3)，內視鏡(評分0至3)及醫生整體評估(評分0至3)；部分MS (評分0至9)-不包括內視鏡評分；內視鏡MS (評分0至3) –黏膜之內視鏡評價；將在治療組之間比較自基線至第12週之各評分之平均變化；具有臨床反應之個體之比例：定義為總MS自基線減少≥ 3及≥ 30%，其中直腸出血子評分自基線減少≥ 1或絕對直腸出血子評分自基線減少≤ 1。將在第12週在治療組之間比較該等比例。具有臨床緩解之個體之比例：定義為MS ≤ 2及不具有個別子評分＞ 1。將在第12週在治療組之間比較該等比例。具有內視鏡反應之個體之比例：定義為MS內視鏡子評分＜
1。將在第12週在治療組之間比較該等比例。在第12週具有組織學緩解之個體之比例。使用營救藥劑：將比較在治療期期間需要各營救藥劑之個體之比例。短發炎性腸病調查表(IBDQ)評分：10個問題IBDQ。將在治療組之間比較自基線至第12週之評分之平均變化。Efficacy assessment: UC-100 score: composite score based on endoscopy, histology, and stool frequency; Ulcerative Colitis Endoscopic Severity Index (UCEIS): Endoscopic score in 3 domains: Vascular pattern (score 1 to 3), bleeding (
生物標誌物：空腹血清C4及FGF-19含量；將進行實驗室分析以評價治療與各生物標誌物之含量之間之關係。此外，將探索各生物標誌物與功效終點之間之關係。Biomarkers: Fasting serum C4 and FGF-19 levels; laboratory analysis will be performed to evaluate the relationship between treatment and levels of each biomarker. In addition, the relationship between each biomarker and efficacy endpoints will be explored.
主要終點：在第12週UC-100之平均變化Primary endpoint: Mean change in UC-100 at
次要終點：在第12週3-分量Mayo評分(基於糞便頻率、直腸出血及內視鏡發現，評分範圍0至9)之平均變化；在第12週評價化合物1或其醫藥上可接受之鹽及安慰劑對潰瘍性結腸炎內視鏡嚴重度指數(UCEIS)之影響；在第12週評價化合物1或其醫藥上可接受之鹽及安慰劑對Robarts組織學指數(RHI)之影響；在第12週總Mayo評分之平均變化；在第12週內視鏡Mayo評分之平均變化；在第12週Mayo評分之糞便頻率及直腸出血子評分之平均變化；如由在第12週總Mayo評分所測定之具有臨床反應之患者之比例；如由在第12週總Mayo評分所測定之具有臨床緩解之患者之比例；在第12週組織學指數之平均變化；在第12週具有組織學緩解之個體之比例；在治療期期間需要各營救藥劑之個體之比例；在第12週發炎性腸病調查表(IBDQ)評分之平均變化；自基線至第12週之空腹血清C4及FGF-19含量之平均變化；自基線至第12週之糞便鈣衛蛋白含量之平均變化；自基線至第12週之血清C-反應性蛋白含量之平均變化。實例 12 ：活體外 FXR 檢定 (TK) 接種 Secondary endpoint: Mean change in 3-component Mayo score (scaled from 0 to 9 based on stool frequency, rectal bleeding, and endoscopic findings) at
將CV-1細胞於具有利用DMEM + 10%炭雙重剝離之FBS之T175燒瓶中以2,000,000個細胞之密度接種及在37℃，5% CO2 下培育18小時(O/N)。轉染 The CV-1 cells using DMEM T175 flask having dual release of 10% of the carbon FBS incubated 18 hours (O / N) + cells were seeded at a density of 2,000,000 and at 37 ℃, 5% CO 2. transfection
於培育18小時後，將T175燒瓶中之培養基用新鮮DMEM + 10%炭超級剝離之血清更換。於聚丙烯管中，將2500 μL OptiMEM (Life Technologies，目錄號31985-062)與hFXR、hRXR、TK-ECRE-luc及pCMX-YFP之表現質粒合併。然後將管短暫渦旋及在室溫下培育5分鐘。將轉染試劑(來自Roche之X-tremeGENE HP，目錄號06 366 236 001)添加至經渦旋之OptiMEM/質粒混合物中及在室溫下培育20分鐘。於培育後，將轉染試劑/DNA混合物複合物添加至T175燒瓶中之細胞中及將細胞在37℃，5% CO2 下培育18小時(O/N)。測試化合物 After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% charcoal super stripped serum. In polypropylene tubes, 2500 μL of OptiMEM (Life Technologies, cat. no. 31985-062) was combined with the expression plasmids for hFXR, hRXR, TK-ECRE-luc and pCMX-YFP. The tubes were then vortexed briefly and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP from Roche, cat no. 06 366 236 001) was added to the vortexed OptiMEM/plasmid mixture and incubated for 20 minutes at room temperature. After incubation, the transfection reagent / DNA complex was added to the mixture in T175 flasks of cells and the cells 37 ℃, 5% CO 2 were incubated for 18 hours (O / N). test compound
將化合物於DMSO中連續稀釋及添加至經轉染之CV-1細胞中。然後將細胞培育18小時。第二天將細胞裂解及檢查發光。Compounds were serially diluted in DMSO and added to transfected CV-1 cells. Cells were then incubated for 18 hours. The cells were lysed the next day and checked for luminescence.
本文中所揭示之示例性化合物之代表性數據呈現於下表中。
為製備適用於藉由注射投與(皮下、靜脈內)之非經腸醫藥組合物，將1至1000 mg本文中所述化合物或其醫藥上可接受之鹽或溶劑化物溶解於無菌水中及然後與10 mL之0.9%無菌鹽水混合。視情況添加適宜緩衝劑以及視情況可選的酸或鹼以調整pH。將混合物併入適用於藉由注射投與之單位劑型。實例 13-B ：口服溶液 To prepare parenteral pharmaceutical compositions suitable for administration by injection (subcutaneous, intravenous), 1 to 1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then Mix with 10 mL of 0.9% sterile saline. Appropriate buffers and optional acids or bases are added as appropriate to adjust the pH. The mixture is incorporated into unit dosage forms suitable for administration by injection. Example 13-B : Oral Solution
為製備用於口服遞送之醫藥組合物，將足量之本文中所述化合物或其醫藥上可接受之鹽添加至水(具有視情況可選的增溶劑、視情況可選的緩衝劑及掩味賦形劑)中，以得到20 mg/mL溶液。實例 13-C ：口服錠劑 To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer, optional buffer, and masking agent). flavor excipient) to obtain a 20 mg/mL solution. Example 13-C : Oral Lozenge
藉由將20至50重量%之本文中所述化合物或其醫藥上可接受之鹽、20至50重量%之微晶纖維素、1至10重量%經低取代之羥丙基纖維素及1至10重量%硬脂酸鎂或其他適宜賦形劑混合來製備錠劑。藉由直接壓縮製備錠劑。將壓縮錠劑之總重量維持在100至500 mg。實例 13-D ：口服膠囊 By combining 20 to 50% by weight of a compound described herein or a pharmaceutically acceptable salt thereof, 20 to 50% by weight of microcrystalline cellulose, 1 to 10% by weight of low-substituted hydroxypropyl cellulose, and 1 To 10% by weight magnesium stearate or other suitable excipients are mixed to prepare lozenges. Tablets are prepared by direct compression. The total weight of the compressed lozenges is maintained at 100 to 500 mg. Example 13-D : Oral Capsules
為製備用於口服遞送之醫藥組合物，將10至500 mg本文中所述化合物或其醫藥上可接受之鹽與澱粉或其他適宜粉末摻合物混合。將混合物併入適用於口服投與之口服劑量單位(諸如硬明膠膠囊)中。To prepare a pharmaceutical composition for oral delivery, 10 to 500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.
於另一實施例中，將10至500 mg本文中所述化合物或其醫藥上可接受之鹽放入4號膠囊或1號膠囊(羥丙基甲基纖維素或硬明膠)中及將膠囊封閉。 實例14：膽管癌及肝細胞癌(源自患者之異種移植物模型)之治療之功效研究In another embodiment, 10 to 500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed in a
將源自患有膽管癌或肝細胞癌之患者之腫瘤組織移植至免疫缺陷小鼠以發展腫瘤，該等腫瘤保留患者腫瘤之組織學/病理學架構及原發驅動子突變及基因表現。監測此等源自患者之異種移植物(PDX)之生長以檢查試驗物品對腫瘤生長之效應。將小鼠右側腹皮下接種來自具有建立之原發人類腫瘤組織之小鼠之2至3 mm直徑塊的新鮮切除的腫瘤。允許腫瘤建立及當平均腫瘤大小達到約150 mm3 時，將小鼠隨機分成治療組及利用媒劑對照或實驗化合物每日經口給藥治療。每週兩次使用電子卡尺以兩個維度量測腫瘤體積及體積使用以下公式測定：V = (L x W x W)/2，其中V為腫瘤體積，L為腫瘤長度(最長腫瘤尺寸)及W為腫瘤寬度(垂直於L之最長腫瘤尺寸)。將小鼠給藥至多4週或直至腫瘤體積超過3000 mm3 或動物之體重減少大於20%。Tumor tissue derived from patients with cholangiocarcinoma or hepatocellular carcinoma is transplanted into immunodeficient mice to develop tumors that retain the histological/pathological architecture and primary driver mutations and gene expression of the patient's tumor. The growth of these patient-derived xenografts (PDX) was monitored to examine the effect of the test article on tumor growth. Freshly excised tumors from 2 to 3 mm diameter blocks from mice with established primary human tumor tissue were inoculated subcutaneously on the right flank of mice. Tumors were allowed to establish and when the average tumor size reached about 150 mm 3, the mice were randomized into treatment groups and administered using a therapeutic or vehicle control daily oral test compound. Tumor volume was measured in two dimensions using an electronic caliper twice a week and volume was determined using the following formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (longest tumor size) and W is tumor width (longest tumor dimension perpendicular to L). Mice were administered up to 4 weeks or until the tumor volumes exceeded 3000 mm 3 or animals body weight reduction more than 20%.
本文中所述之實例及實施例僅出於說明目的及對熟習此項技術者建議之各種修改或變化包含於本申請案之精神及權限及隨附申請專利範圍之範圍內。實例 15 ：膽汁鬱積及原發性硬化性膽管炎 (Mdr2-/- 小鼠模型 ) 之治療之功效研究 The examples and embodiments described herein are for illustrative purposes only and various modifications or variations are suggested to those skilled in the art to be included within the spirit and purview of this application and the scope of the appended claims. Example 15 : Efficacy study of treatment of cholestasis and primary sclerosing cholangitis (Mdr2 -/- mouse model )
耐多種藥物性3 (MDR3)負責將磷脂轉運至膽汁。人類中此轉運蛋白上之突變可導致進行性家族性肝內膽汁鬱積(PFIC3)。小鼠同源物MDR2之基因敲除相似地導致小鼠之膽汁鬱積及纖維化(Fickert 2004 Gastroenterology 127 261)。此模型可用於評估FXR促效劑減少膽汁鬱積及肝損傷之功效(Baghdasaryan 2011 Hepatology 54 1313)。 8週齡之MDR2-/-
小鼠展示升高之血清膽汁酸、肝酶且顯示肝纖維化及發炎之證據。為檢查FXR促效劑之治療功效，可將8週齡敲除小鼠藉由口服管飼給藥化合物。可藉由檢查對血清膽汁酸、肝酶(ALT，ALP)及膽紅素之效應來監測功效。另外功效點可包括肝組織病理學分析及發炎、膽管增生及肝纖維化之評分。 實例16：評價化合物1單獨或與SGLT-2抑制劑組合於患有2型糖尿病(T2DM)及非酒精性脂肪性肝炎(NASH)之患者中之2期研究Multidrug resistance 3 (MDR3) is responsible for the transport of phospholipids to bile. Mutations in this transporter in humans lead to progressive familial intrahepatic cholestasis (PFIC3). Knockout of the mouse homolog MDR2 similarly results in cholestasis and fibrosis in mice (Fickert 2004 Gastroenterology 127 261). This model can be used to assess the efficacy of FXR agonists in reducing cholestasis and liver injury (Baghdasaryan 2011 Hepatology 54 1313). MDR2 -/- mice at 8 weeks of age displayed elevated serum bile acids, liver enzymes and showed evidence of liver fibrosis and inflammation. To examine the therapeutic efficacy of FXR agonists, 8-week-old knockout mice can be administered compounds by oral gavage. Efficacy can be monitored by examining effects on serum bile acids, liver enzymes (ALT, ALP) and bilirubin. Additional efficacy points may include liver histopathological analysis and scores for inflammation, bile duct hyperplasia, and liver fibrosis. Example 16:
描述患有非酒精性脂肪性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)之糖尿病人之臨床試驗之非限制性實例。患有2型糖尿病及非酒精性脂肪性肝炎之個體將參與此研究。Non-limiting examples of clinical trials in diabetics with nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD) are described. Individuals with
主要目標：評價化合物1或其醫藥上可接受之鹽單獨或與恩格列淨(empagliflozin)組合於患有T2DM及NASH之個體中之安全性及耐受性。Primary objective: To evaluate the safety and tolerability of
次要目標：表徵化合物1單獨或與恩格列淨組合之藥物動力學(PK)。表徵化合物1單獨或與恩格列淨組合之藥效動力學(PD)。研究化合物1單獨或與恩格列淨組合對肝脂肪含量及NASH纖維化生物標誌物之影響。Secondary objective: To characterize the pharmacokinetics (PK) of
研究設計：評價化合物1 (50 mg)單獨或與恩格列淨(25 mg)組合持續12週之隨機多中心研究。化合物1之分配將係雙盲及安慰劑對照。將恩格列淨以開放方式併入治療組中之兩者：指定接收恩格列淨之個體將以10 mg/天開始持續2週。除非藉由安全性或耐受性擔心限制，否則恩格列淨之劑量將增加至25 mg持續治療持續時間之剩餘。針對安全性或耐受性發現，將允許個別個體之向下滴定至10 mg一次。每個治療組將募集約30個個體。 研究群體Study Design: A randomized multicenter study evaluating Compound 1 (50 mg) alone or in combination with empagliflozin (25 mg) for 12 weeks. The assignment of
納入標準：個體必須滿足下列標準以有資格參與研究：1.在簽署知情同意書時18至75歲男性及女性。2.在任何研究相關評估/程序之前理解及自願簽署知情同意書。3.基於下列標準中之一者診斷為NASH：於篩選之12個月內組織學證實之NASH：NAFLD活動評分(NAS) ≥ 4，具有脂肪變性、發炎及球囊擴張各者中之至少1點。於募集之6個月內磁共振彈性成像(MRE)顯示kPa ≥ 2.61或多參數MRI (即，肝多重掃描)顯示鐵校正T1 (cT1) ＞ 830 ms。暫態彈性成像(TE，FibroScan)與肝硬度≥ 8.5 kPa及於募集之3個月內獲得之控制衰減參數(CAP) ＞ 300 dB/m。4.在篩選期間藉由磁共振成像-質子密度脂肪分數(MRI-PDFF)量測之肝脂肪含量≥8%。5.在篩選期間診斷T2DM ≤10年，與血紅蛋白A1c ≤ 9.5%。6.在篩選時總膽紅素及直接膽紅素之含量≤值得注意範圍之上限。若在篩選時，直接膽紅素、網織紅細胞計數及血紅蛋白之含量於正常限制內，則可募集具有異常總膽紅素含量之患有吉爾伯特氏(Gilbert’s)症候群之個體。7. ALT、ALP、AST及總膽紅素穩定性：在給藥開始之前獲得之兩個值相距≥14天及此等兩個值之間之計算之平均值≤值得注意範圍之上限；或若該計算之平均值＞值得注意範圍之上限，則該等兩個值之間差異≤ 3x。該等值中至少一者必須源自篩選安全性實驗室；篩選之3個月內之歷史結果可用於提供資格之第二值。若歷史結果不可得，則在篩選期間必須進行重複肝全套檢查。8.在篩選期間必須滿足下列標準之另外實驗值：血小板計數≥ 150 x 109
/L；除非個體目前正在採用抗凝劑，否則國際標準化比率(INR) ＜ 1.4；血漿丙胺酸胺基轉移酶(ALT) ≥ 30 U/L且≤ 150 U/L；血漿天冬胺酸胺基轉移酶(AST) ≥ 20 U/L且≤ 150 U/L。9.藉由腎病飲食修改(MDRD)方程式估計之腎小球過濾速率(eGFR)係≥ 60 mL / min / 1.73 m2
且在篩選期間無臨床顯著尿分析發現結果(例如，蛋白尿、血尿)。10.在募集之前之30天(或5個藥物消除半衰期)內無研究藥劑。11.在募集之前，許可服用他汀(針對排除他汀參見排除標準部分)之個體必須以穩定劑量至少8週。12. 個體可服用＜ 800 IU/天之劑量之維生素E，條件為該劑量在募集之前為穩定劑量持續至少12週。13.願意且能服從研究隨訪時程表及其他協定要求。Inclusion Criteria: Individuals must meet the following criteria to be eligible to participate in the study: 1. Males and females between the ages of 18 and 75 at the time of signing the informed consent. 2. Understand and voluntarily sign informed consent prior to any study-related assessments/procedures. 3. NASH diagnosed based on one of the following criteria: Histologically confirmed NASH within 12 months of screening: NAFLD Activity Score (NAS) ≥ 4, with at least 1 of each of steatosis, inflammation and balloon dilatation point. Magnetic resonance elastography (MRE) with kPa ≥ 2.61 or multiparametric MRI (ie, liver multiple scan) with iron-corrected T1 (cT1) > 830 ms within 6 months of recruitment. Transient elastography (TE, FibroScan) with liver stiffness ≥ 8.5 kPa and controlled attenuation parameter (CAP) > 300 dB/m obtained within 3 months of recruitment. 4. Liver fat content ≥8% as measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) during screening. 5. Diagnosed T2DM ≤10 years during screening, with hemoglobin A1c ≤9.5%. 6. The content of total bilirubin and direct bilirubin during screening is less than or equal to the upper limit of the noteworthy range. If the direct bilirubin, reticulocyte count and hemoglobin levels are within normal limits at screening, individuals with Gilbert's syndrome with abnormal total bilirubin levels can be recruited. or If the calculated mean > the upper limit of the noteworthy range, the difference between the two values is ≤ 3x. At least one of these equivalent values must be derived from a screening safety laboratory; historical results within 3 months of screening may be used to provide a second value for eligibility. If historical results are not available, repeat liver tests must be performed during screening. 8. Additional experimental values of the following criteria must be met during screening: Platelet count ≥ 150 x 10 9 /L; International Normalized Ratio (INR) < 1.4 unless the individual is currently taking anticoagulants; Plasma alanine aminotransferase (ALT) ≥ 30 U/L and ≤ 150 U/L; plasma aspartate aminotransferase (AST) ≥ 20 U/L and ≤ 150 U/L. 9. modified by Diet in Renal Disease (the MDRD) equation of the estimated glomerular filtration rate (the eGFR) based ≥ 60 mL / min / 1.73
排除標準：具有下列中之任一者之個體將自參與該研究排除：1.顯著肝病(例如，酒精性肝病、病毒性肝炎等)或肝移植史。2.任何先前肝活組織檢查時存在肝硬化(4期肝硬化)。3.過量消耗酒精，如由下列中之任一者定義：於篩選之6個月內針對男性飲酒≥ 294 g/週(或約3次飲酒/天)；於篩選之6個月內針對女性飲酒≥ 196 g/週(或約2次飲酒/天)；在篩選期間基於研究者判斷利用或不利用針對酒精存在之陽性測試不能可靠定量酒精消耗。4.在篩選之3個月內使用任何胰島素(可注射或吸入)、SGLT-2抑制劑或類升糖素胜肽1 (GLP-1，可注射或口服)產品持續＞7天。5.在篩選之前之6個月內體重損失＞ 10%或在篩選期間體重損失＞ 5%。6.鹼性磷酸酶(ALP) ＞ 2x值得注意範圍之上限。7.在篩選之前之12個月內使用與引起NAFLD歷史相關聯之藥物(例如，胺碘酮、胺甲喋呤、全身糖皮質激素、四環素、他莫西芬、以高於用於激素替代之彼等之劑量之***、合成代謝類固醇、丙戊酸及其他已知肝毒素)超過4個連續週。8.合併使用為具有窄治療指數之CYP3A4物質之藥物(例如，阿普唑崙(alprazolam)、胺氯地平(amlodipine)、阿托伐他汀(atorvastatin)、卡巴西平(carbamazepine)、秋水仙鹼(colchicine)、環孢菌素(cyclosporine)、雙氫麥角胺(dihydroergotamine)、地爾硫卓(diltiazem)、麥角胺(ergotamine)、非洛地平(felodipine)、芬太尼(fentanyl)、咪達唑崙(midazolam)、洛伐他汀(lovastatin)、洛美他派(lomitapide)、硝苯地平(nifedipine)、匹莫齊特(pimozide)、奎尼丁(quinidine)、辛伐他汀(simvastatin))。9.伴隨使用為強或中度CYP3A4抑制劑之藥物(例如，阿瑞匹坦(aprepitant)、波普瑞韋(boceprevir)、西咪替丁、環丙沙星(ciprofloxacin)、克拉黴素(clarithromycin)、克黴唑(clotrimazole)、可比司他(cobicistat)、考尼伐坦(conivaptan)、克唑替尼(crizotinib)、環孢菌素、地爾硫卓、決奈達隆(dronedarone)、紅黴素(erythromycin)、氟康唑(fluconazole)、氟伏沙明(fluvoxamine)、艾代拉裡斯(idelalisib)、伊馬替尼(imatinib)、茚地那韋(indinavir)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、奈法唑酮(nefazodone)、奈非那韋(nelfinavir)、泊沙康唑(posaconazole)、利托那韋(ritonavir)、沙奎那韋(saquinavir)、特拉匹韋(telaprevir)、泰利黴素(telithromycin)、維拉帕米(verapamil)、伏立康唑(voriconazole))。10.合併消耗具有研究藥物之葡萄柚汁。11.對研究藥物錠劑之成分中之任一者(化合物1及恩格列淨)過敏史。12.對恩格列淨之任何禁忌，如處方資訊上所列。13.任何酮酸中度史。14.於篩選之5年內尿膿毒病或腎盂腎炎＞2次發作史。15.不能經歷或對MRI禁忌，包括不可利用抗焦慮藥治療之幽閉恐懼症。16.排除研究順從之任何顯著醫療狀況、物質濫用、精神病或社會情況。17.若個體將參與該研究，則將其置於不可接受風險之任何狀況，包括存在實驗室異常。18.混淆自該研究解釋數據之能力之任何狀況。Exclusion Criteria: Subjects with any of the following will be excluded from participation in the study: 1. Significant liver disease (eg, alcoholic liver disease, viral hepatitis, etc.) or a history of liver transplantation. 2. Presence of cirrhosis (
研究長度：約20週，其包含4週篩選期，12週治療期，及4週隨訪期。Study Length: Approximately 20 weeks, comprising a 4-week screening period, a 12-week treatment period, and a 4-week follow-up period.
研究治療：化合物1將藉由錠劑每日一次經口投與。恩格列淨亦將藉由錠劑每日一次經口投與。個體將接受治療12週。 程序Study Treatment:
篩選(第-28天至第-1天)：該篩選期可不超過28天。於獲得知情同意後，將評價個體人口統計、醫療史(包含NASH疾病史)、合併用藥、酒精/藥物篩選、體檢、身高/體重/體質指數(BMI)、生命體徵、12-導聯心電圖(ECG)、血清化學/血液學、凝聚、尿分析、妊娠測試(若適用)及MRI-PDFF (若指定，則加上TE)以評估個體資格。 Screening (Day -28 to Day -1): The screening period may not exceed 28 days. Following informed consent, individual demographics, medical history (including NASH disease history), concomitant medications, alcohol/drug screening, physical examination, height/weight/body mass index (BMI), vital signs, 12-lead ECG ( ECG), serum chemistry/hematology, coagulation, urinalysis, pregnancy test (if applicable), and MRI-PDFF (plus TE if specified) to assess individual eligibility.
治療(第1天至第84天)：可於第1天給藥之前之7天內進行基線實驗及若於給藥之7天內進行篩選實驗，則不必重複。除非針對不可接受毒性，撤回同意，調查者或醫療監督員決定較早停止或終止該研究，否則自第1天至第84天個體將接受口服研究藥物。將進行下列治療期評估及程序：合併用藥、飲食、活性水平、靶向體檢、身高/體重/BMI、生命體徵、安全性評估(例如，不良事件(AE)/實驗室/生命體徵)、血清化學/血液學、凝集、尿分析、妊娠測試(若適用)、NASH纖維化生物標誌物、PK及PD取樣(於個體之子集中)及遵從協定。 Treatment (
治療結束(第84天)：在第84天(±3天)或若早期停止給藥，則更早進行下列治療結束(EOT)評估及程序：合併用藥、飲食、活性水平、靶向體檢、身高/體重/BMI、生命體徵、ECG、安全性評估(例如，AE/實驗室/生命體徵)、血清化學/血液學、凝集、尿分析、妊娠測試(若適用)、MRI-PDFF、NASH纖維化生物標誌物、PK及PD取樣(於個體之子集中)及遵從協定。 End of Treatment (Day 84): On Day 84 (±3 days) or earlier if dosing was discontinued earlier, perform the following End of Treatment (EOT) assessments and procedures: concomitant medications, diet, activity levels, targeted physicals, Height/weight/BMI, vital signs, ECG, safety assessment (eg, AE/lab/vital signs), serum chemistry/hematology, agglutination, urinalysis, pregnancy test (if applicable), MRI-PDFF, NASH fiber Chemical biomarkers, PK and PD sampling (in a subset of individuals) and protocol compliance.
研究結束/隨訪(第112天)：於研究藥物給藥後為了安全個體將被隨訪及評估活性徵兆(例如，MRI-PDFF、NASH纖維化生物標誌物等)之可逆性持續28天。將在第112天(±5天)進行下列研究結束(EOS) /隨訪評估及程序：合併用藥、飲食、活性水平、靶向體檢、身高/體重/BMI、安全性評估(例如，AE/實驗室/生命體徵)、血清化學/血液學、凝集、尿分析、妊娠測試(若適用)、MRI-PDFF、NASH纖維化生物標誌物、及PD取樣(於個體之子集中)。 安全性評估之概觀End of Study/Follow-Up (Day 112): Subjects will be followed for safety and assessed for reversibility of signs of activity (eg, MRI-PDFF, NASH fibrosis biomarkers, etc.) for 28 days following study drug dosing. The following end-of-study (EOS)/follow-up assessments and procedures will be performed on Day 112 (±5 days): concomitant medication, diet, activity level, targeted physical examination, height/weight/BMI, safety assessment (eg, AE/experimental) laboratory/vital signs), serum chemistry/hematology, agglutination, urinalysis, pregnancy testing (if applicable), MRI-PDFF, NASH fibrosis biomarkers, and PD sampling (in a subset of individuals). Overview of Security Assessment
安全性評估將包括收集不良事件、生命體徵及身體檢查，12-導聯ECG，實驗室評估及合併治療之驗證。若臨床指定，則可更頻繁進行實驗室測試及程序。Safety assessment will include collection of adverse events, vital signs and physical examination, 12-lead ECG, laboratory assessment and validation of concomitant therapy. Laboratory tests and procedures may be performed more frequently if clinically indicated.
化合物1或恩格列淨之劑量中斷可發生，但是不允許化合物1之劑量減少。若下列情況中之任一者出現，則將暫停對個別患者之化合物1給藥：若ALT或AST基線平均值(BLM) ＜ 2x ULN，若ALT或AST增加至＞ 5x BLM，則停止；若ALT或AST BLM ≥ 2x ULN且＜ 5x ULN，若ALT或AST增加至＞ 3x BLM，則停止；若ALT或AST增加至＞ 2x BLM且伴隨以下任一者：(a)總膽紅素增加至＞ 2x BLM或(b) INR增加＞ 0.2；與肝損傷一致之徵兆或症狀(例如，疲勞、噁心、嘔吐、右上腹疼痛或壓痛、發燒、皮疹及/或嗜酸性白血球增多[＞ 5%])且伴隨ALT、AST或總膽紅素之升高。ALT、ALP、AST及總膽紅素之基線平均值(BLM)經定義為篩選值與第1天值之間之平均值以確定劑量懸掛。 附加評估之概觀Dose interruptions for
藥物動力學(PK)評估：採集血液樣品及分析PK參數(Cmax 、tmax 、t½、Ctrough 、CLss/F、Cavg(0-24 h) 、AUC0-tau 、AUC0-t 、AUC0-inf )，該等參數將藉由非室分析估計。Pharmacokinetic (PK) assessment: blood samples were collected and analyzed PK parameters (C max, t max, t½ , C trough, CLss / F, C avg (0-24 h), AUC 0-tau, AUC 0-t, AUC 0-inf ), these parameters will be estimated by non-compartmental analysis.
藥效動力學(PD)評估：採集血液樣品及分析PD標誌物。Pharmacodynamic (PD) assessment: Blood samples were collected and analyzed for PD markers.
纖維化生物標誌物評估：源自量測透明質酸、III型前膠原胺基端肽(PIIINP)、金屬蛋白酶之組織抑制劑1(TIMP-1)作為纖維化之生物標誌物之增強之肝纖維化(ELF)評分。III型膠原之前肽(Pro-C3)作為纖維化之生物標誌物。NAFLD纖維化評分(NFS)以識別晚期纖維化(年齡、高血糖、體質指數、血小板計數、白蛋白及AST/ALT比率)。FIB-4評分(年齡、AST、ALT及血小板計數)以對纖維化程度進行分級。Fibrosis biomarker assessment: enhanced liver derived from measuring hyaluronic acid, procollagen type III aminotelopeptide (PIIINP), tissue inhibitor of metalloproteinase 1 (TIMP-1) as biomarkers of fibrosis Fibrosis (ELF) score. Pre-collagen type III peptide (Pro-C3) as a biomarker of fibrosis. NAFLD Fibrosis Score (NFS) to identify advanced fibrosis (age, hyperglycemia, body mass index, platelet count, albumin and AST/ALT ratio). FIB-4 score (age, AST, ALT and platelet count) to grade the degree of fibrosis.
探索性活性分析：將針對mITT群體使用MRI-PDFF及NASH纖維化生物標誌物(包括ELF評分、TIMP-1、Pro-C3、NAFLD纖維化評分及FIB-4評分)探索化合物1之活性。將概述針對MRI-PDFF之基線、劑量後及變化及自基線之變化%。將在基線時及基線訪問後之NASH纖維化生物標誌物製錶及列出。 實例17：化合物1及GLP-1類似物於患有非酒精性脂肪性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)之成人中之安全性、耐受性及功效Exploratory Activity Analysis: The activity of
描述患有非酒精性脂肪性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)之糖尿病人之臨床試驗之非限制性實例。Non-limiting examples of clinical trials in diabetics with nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD) are described.
目的：此研究之目的為評價化合物1及利拉魯肽組合療法於患有NASH或NAFLD之糖尿病人中之安全性、耐受性及功效。Objective: The objective of this study was to evaluate the safety, tolerability and efficacy of
研究設計：約10至30個患者之3個群組各將接受化合物1、利拉魯肽或二者或安慰劑至多12週。Study Design: Each of 3 cohorts of approximately 10 to 30 patients will receive
一個群組將每日一次接受約50 mg化合物1。一個群組將接受匹配安慰劑。One cohort will receive approximately 50 mg of
一個群組將接受約50 mg化合物1及約1.2 mg利拉魯肽，二者均每日一次投與。一個群組將接受約1.2 mg利拉魯肽及匹配化合物1之安慰劑，二者均每日一次投與。One cohort will receive about 50 mg of
納入標準：(1) 18至75歲男性及女性；(2)患有輕度-中度2型糖尿病(T2DM)之個體(HbA1c 7至9%)；(3)基於活組織檢查或成像，診斷為NASH；(4)在篩選期間，藉由MRI-PDFF量測之肝脂肪含量＞
10%；(5)於研究藥物之第一劑量之前之30天(或5個藥物消除半衰期)內無研究劑；(6)在研究藥物之第一劑量之前，許可服用他汀之個體必須以穩定劑量至少3個月；(7) 個體可服用＜ 800 IU/天之劑量之維生素E，條件為該劑量在研究藥物之第一劑量之前為穩定劑量持續至少3個月。Inclusion criteria: (1) men and women aged 18 to 75; (2) individuals with mild-to-
排除標準：(1)任何其他肝病(例如，酒精性肝病、病毒性肝炎等)之歷史或存在或肝移植史；(2)在任何肝活組織檢查時存在肝硬化(4期肝硬化)；(3) 過量消耗酒精；(4)在篩選之前之6個月內體重損失＞ 10%或在篩選期間體重損失＞ 5%；(5)合併使用為強或中度CYP3A4抑制劑或具有窄治療指數之CYP3A4物質之藥物；(6)合併使用SGLT2抑制劑或GLP-1類似物。Exclusion criteria: (1) history or presence of any other liver disease (eg, alcoholic liver disease, viral hepatitis, etc.) or liver transplantation; (2) presence of cirrhosis (
功效評估：藉由MRI-PDFF及NASH生物標誌物量測之肝脂肪含量%。血糖控制。Efficacy assessment: % liver fat content measured by MRI-PDFF and NASH biomarkers. Blood sugar control.
安全性評估：安全性評估將包括收集不良事件、生命體徵及身體檢查，12-導聯ECG，實驗室評估及伴隨治療之驗證。若臨床指定，則可更頻繁進行實驗室測試及程序。Safety Assessment: Safety assessment will include collection of adverse events, vital signs and physical examination, 12-lead ECG, laboratory assessment and validation of concomitant therapy. Laboratory tests and procedures may be performed more frequently if clinically indicated.
藥物動力學評估：根據PK取樣時程表採集血液樣品。PK參數(Cmax 、tmax 、t½、Ctrough 、CLss/F、Cavg(0-24 h) 、AUC0-tau 、AUC0-t 、AUC0-inf )將藉由非室分析估計。Pharmacokinetic Assessment: Blood samples were collected according to the PK sampling schedule. PK parameters (C max, t max, t½ , C trough, CLss / F, C avg (0-24 h), AUC 0-tau, AUC 0-t, AUC 0-inf) The estimated by non-compartmental analysis.
藥效動力學(PD)評估：根據PD (C4、FGF-19、膽汁酸)取樣時程表採集血液樣品。Pharmacodynamic (PD) assessment: Blood samples were collected according to the PD (C4, FGF-19, bile acids) sampling schedule.
生物標誌物評估：藉由以下量測纖維化：源自量測透明質酸、III型前膠原胺基端肽(PIIINP)、金屬蛋白酶之組織抑制劑1 (TIMP-1)作為纖維化之生物標誌物之增強之肝纖維化(ELF)評分；III型膠原之前肽(Pro-C3)作為纖維化之生物標誌物； NAFLD纖維化評分(NFS)以識別晚期纖維化(年齡、高血糖、體質指數、血小板計數、白蛋白及AST/ALT比率)； FIB-4評分(年齡、AST、ALT及血小板計數)以對纖維化程度進行分級。Biomarker assessment: Fibrosis was measured by: Derived from the measurement of hyaluronic acid, procollagen type III aminotelopeptide (PIIINP), tissue inhibitor of metalloproteinase 1 (TIMP-1) as fibrotic organisms Enhanced liver fibrosis (ELF) score for markers; precollagen type III peptide (Pro-C3) as a biomarker for fibrosis; NAFLD fibrosis score (NFS) to identify advanced fibrosis (age, hyperglycemia, constitution index, platelet count, albumin and AST/ALT ratio); FIB-4 score (age, AST, ALT and platelet count) to grade the degree of fibrosis.
膽汁酸組成：血清膽汁酸(藉由LC-MS量測之總膽汁酸及15種膽汁酸小組)；特定比率及分析方法。Bile acid composition: Serum bile acids (total bile acids and panel of 15 bile acids measured by LC-MS); specific ratios and analytical methods.
主要終點：不良事件(AE)、嚴重不良事件(SAE)及實驗室異常之發生率、嚴重度及結果。Primary endpoint: incidence, severity and outcome of adverse events (AEs), serious adverse events (SAEs) and laboratory abnormalities.
探索性終點：使用MRI-PDFF藉由肝脂肪定量估計之活性。Exploratory endpoint: Activity estimated by hepatic fat quantification using MRI-PDFF.
研究長度：約12週，排除篩選期及隨訪期。Study Length: Approximately 12 weeks, excluding screening and follow-up periods.
本文中所述之實例及實施例僅出於說明目的及對熟習此項技術者建議之各種修改或變化包含於本申請案之精神及權限及隨附申請專利範圍之範圍內。The examples and embodiments described herein are for illustrative purposes only and various modifications or variations are suggested to those skilled in the art to be included within the spirit and purview of this application and the scope of the appended claims.
圖1顯示於每日一次口服給藥14天後血漿中之化合物1藥物含量。Figure 1 shows
圖2顯示利用指定量之化合物1給藥之健康患者中之總膽汁酸的減少%。Figure 2 shows the % reduction in total bile acids in healthy patients dosed with the indicated amounts of
圖3A顯示於投與後接受指定劑量之化合物1持續24小時之時間之健康患者中之C4含量的變化。Figure 3A shows changes in C4 levels in healthy patients receiving the indicated doses of
圖3B顯示於投與後接受指定劑量之化合物1持續24小時之時間之健康患者中之FGF-19含量的變化。Figure 3B shows changes in FGF-19 levels in healthy patients receiving the indicated doses of
圖4顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之相對肝脂肪變化。Figure 4 shows relative liver fat changes in NASH patients receiving a daily dose of 50 mg of
圖5A顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之LDL-C含量自基線之變化%。Figure 5A shows the % change from baseline in LDL-C levels in NASH patients receiving a daily 50 mg dose of
圖5B顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之甘油三酯含量自基線之變化%。Figure 5B shows the % change from baseline in triglyceride levels in NASH patients receiving a daily 50 mg dose of
圖5C顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之HDL-C含量自基線之變化%。Figure 5C shows the % change from baseline in HDL-C levels in NASH patients receiving a daily 50 mg dose of
圖6A顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之ALT含量自基線之變化%。Figure 6A shows the % change from baseline in ALT levels in NASH patients receiving a daily 50 mg dose of
圖6B顯示歷時28天時間接受每日50 mg劑量之化合物1之NASH患者中之GGT含量自基線之變化%。Figure 6B shows the % change from baseline in GGT levels in NASH patients receiving a daily 50 mg dose of
圖7顯示利用50 mg之化合物1給藥之健康及NASH患者之藥物動力學結果。Figure 7 shows the pharmacokinetic results in healthy and NASH patients dosed with 50 mg of
圖8顯示歷時12週時間接受每日50 mg劑量之化合物1之NASH患者中之相對肝脂肪變化。Figure 8 shows relative liver fat changes in NASH
圖9顯示歷時12週時間接受每日80 mg劑量之化合物1之NASH患者中之相對肝脂肪變化。Figure 9 shows relative liver fat changes in NASH
圖10顯示歷時12週時間接受每日50 mg劑量之化合物1之NASH患者中之肝脂肪含量的個別變化。Figure 10 shows individual changes in liver fat content in NASH patients receiving a daily 50 mg dose of
圖11顯示歷時12週時間接受每日80 mg劑量之化合物1之NASH患者中之肝脂肪含量的個別變化。Figure 11 shows individual changes in liver fat content in NASH patients receiving a daily 80 mg dose of
圖12顯示歷時12週時間接受每日50 mg或80 mg劑量之化合物1之NASH患者之體重損失。Figure 12 shows weight loss in NASH
圖13顯示於向NASH患者投與化合物1後第12週使用接受者操作特徵下面積(AUC)分析之肝脂肪含量(LFC)臨限值及性能用於預測≥30%相對LFC減少。Figure 13 shows liver fat content (LFC) thresholds and performance using area under receiver operating characteristic (AUC) analysis for predicting > 30% relative LFC reduction at
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