CN107001439B - Gip激动剂化合物及方法 - Google Patents
Gip激动剂化合物及方法 Download PDFInfo
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- CN107001439B CN107001439B CN201580059529.3A CN201580059529A CN107001439B CN 107001439 B CN107001439 B CN 107001439B CN 201580059529 A CN201580059529 A CN 201580059529A CN 107001439 B CN107001439 B CN 107001439B
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000005156 substituted alkylene group Chemical group 0.000 description 1
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- 125000000542 sulfonic acid group Chemical group 0.000 description 1
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- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
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Abstract
本发明涉及具有GIP激动剂活性的酰化GIP类似物,及其在治疗代谢紊乱中的用途。
Description
技术领域
本发明涉及对GIP受体具有激动剂活性的化合物及其在治疗代谢紊乱中的用途。
背景技术
糖尿病和肥胖是日益增加的全球健康问题,其与多种其他疾病相关,特别是心血管疾病(CVD)、阻塞性睡眠呼吸暂停、中风、外周动脉疾病、微血管并发症和骨关节炎。全世界有2.46亿人患有糖尿病,估计到2025年将有3.8亿人患有糖尿病。许多具有额外的心血管风险因素,包括高/异常LDL和甘油三酯以及低HDL。心血管疾病在糖尿病患者的死亡率中占约50%,与肥胖和糖尿病相关的发病率和死亡率强调了医学上对于有效的治疗选择的需求。
葡萄糖依赖性促胰岛素多肽(“GIP”,也称为“胃抑制性多肽”)是响应于经口营养摄入而由小肠的肠内分泌K细胞分泌到血流中的42个残基的肽。GIP抑制胃酸的分泌,并且已经显示其是经口葡萄糖摄入后胰腺β细胞分泌胰岛素的强效刺激物(“肠促胰岛素效应”)(Creutzfeldt,W.等,1979,Diabetologia,16:75-85)。
通过摄入葡萄糖和其他营养物质诱导的胰岛素释放是由于激素和神经因素两者(Creutzfeldt,W.等,1985,Diabetologia,28:565-573)。已经提出数种胃肠调节肽作为肠促胰岛素,在这些候选物中,只有GIP和胰高血糖素样肽1(“GLP-1”)似乎满足了被认为是餐后胰岛素释放的生理刺激物的要求(Nauck等,1989,J.Clin.Endocrinol Metab.,69:654-662)。已经表明,GIP和GLP-1的组合效应足以解释肠胰岛轴的全部肠促胰岛素效应(Fehmann,H.C等,1989,FEBS Lett,252:109-112)。
如本领域技术人员所公知的,GIP的已知和潜在用途是多种多样的。因此,为了引发激动剂效应,本发明化合物的施用可以具有与GIP本身相同的效应和用途。GIP的这些不同用途可归纳如下:治疗选自以下的疾病:1型糖尿病、2型糖尿病(Visboll,T.,2004,Dan.Med.Bull,51:364-70)、胰岛素抵抗(WO 2005/082928)、肥胖(Green,B.D.等,2004,Current Pharmaceutical Design,10:3651-3662)、代谢紊乱(Gault,V.A.等,2003,Biochem.Biophys.Res.Commun.,308:207-213)、中枢神经***疾病、神经退行性疾病、充血性心力衰竭、低血糖症以及期望减少食物摄入和减轻体重的紊乱。在胰岛中,GIP不仅急剧增强胰岛素分泌,而且还通过增强胰岛素原的转录和翻译来刺激胰岛素的产生(Wang等,1996,Mol Cell.Endocrinol,116:81-87),并且增强胰腺β细胞的生长和存活(Trumper等,2003,Diabetes,52:741-750)。除了影响胰腺以增强胰岛素分泌之外,GIP还直接影响胰岛素靶组织以降低血浆葡萄糖:增加脂肪(Eckel等,1979,Diabetes,28:1141-1142)和肌肉(O′Harte等,1998,J.Endocrinol,156:237-243)中的葡萄糖摄取并且抑制肝葡萄糖产生(Elahi,D.等,1986,Can.J.Physiol.Pharmacol,65:A18)。
最近,据报道,当共施用GLP-1和GIP时,与GLP-1激动剂治疗相关的体重减轻得到增强(Finan,Sci Transl Med.2013;5(209):209ra151.Irwin N等,2009,Regul Pept;153:70-76.Gault等,2011,Clin Sci(Lond);121:107-117)。例如,在亚长期共施用酰化GIP激动剂和酰化GLP-1激动剂后,Finan和同事证明了在饮食诱导的肥胖(DIO)小鼠中显著减轻了体重。共施用比单独的任一单激动剂更大程度地降低了体重和脂肪质量。证据还表明,GLP-1和GIP对血糖控制具有累加效应(Gault等,2011,Clin Sci(Lond);121:107-117)。Gault等人的研究表明,在ob/ob小鼠的腹膜内葡萄糖耐量测试中,与单独注射GLP-1激动剂或GIP激动剂相比,GLP-1类似物和酰化GIP类似物的亚长期共施用导致更多的葡萄糖降低和促胰岛素作用。因此,当与GLP-1受体激动剂(作为相同的药物制剂的一部分或作为单独的制剂)组合施用时,GIP激动剂可以特别有效地改善血糖控制和减轻体重。
然而,未修饰的GIP作为治疗剂的应用受到约2分钟的短体内半衰期的限制(Said和Mutt,1970,Science,169:1217-1218)。在血清中,GIP和GLP-1两种肠促胰岛素都被二肽基肽酶IV(“DPPIV”)降解。提高GIP对蛋白水解的稳定性不仅保持了GIP对其受体的活性,而更重要的是防止GIP片段的产生,其中一些充当了GIP受体拮抗剂(Gault等,2002,J.Endocrinol,175:525-533)。已报告的修饰包括通过N末端酪氨酸的修饰(O′Harte等,2002,Diabetologia,45:1281-1291)、2位丙氨酸的突变(Hinke等,2002,Diabetes,51:656-661)、3位谷氨酸的突变(Gault等,2003,Biochem.Biophys.Res.Commun.,308:207-213)以及13位丙氨酸的突变(Gault等,2003,Cell Biol.International,27:41-46)来保护GIP的N末端免于被DPPIV蛋白水解。
以下专利申请已提交并且涉及GIP类似物对多种靶器官功能的影响及其作为治疗剂的潜在用途:PCT公开WO 00/58360公开了刺激胰岛素释放的GIP的肽基类似物。特别地,该申请公开了包含GIP的N末端至少15个氨基酸残基的特定肽基类似物(I-42)。PCT公开WO03/082898公开了GIP的C末端截短的片段和N末端修饰的类似物,以及具有减少的肽键或接近DPPFV特异性切割位点的氨基酸改变的多种GIP类似物。该申请进一步公开了在GIP的潜在受体结合位点之间具有不同接头的类似物。该申请的化合物据称可用于治疗GIP受体介导的病症,如非胰岛素依赖性糖尿病和肥胖。此外,在如本文所示的本发明化合物的其他治疗效果中,更严格地控制血浆葡萄糖水平可以预防长期的糖尿病并发症,从而为患者提供改善的生活质量。除了改善血糖控制之外,GIP也可以增强GLP-1介导的体重减轻。已经显示GIP类似物与例如PEG(聚乙二醇)的缀合延长了体内半衰期,但已经报道了聚乙二醇化的药物产品如干扰素β和利巴韦林具有潜在副作用(J Clin Gastroenterol.2004年9月;38(8):717-22,Gut 2006;55:1350-1359doi:10.1136/gut.2005.076646)。
因此,仍然需要改进和安全的GIP类似物,其在制剂中是稳定的,并且其由于对蛋白水解的易感性降低和清除率降低而具有长的体内半衰期,同时保持与GIP受体的结合亲和力以引起激动剂效果。
发明内容
本发明涉及GIP类似物,其可具有如在体外效力测定中所评估的改变的GIP活性性质,以及如在小鼠的体内研究中所评估的改变的(优选增加的)终末消除半衰期(T1/2)。
已经发现,本发明的GIP受体激动剂优于现有的GIP类似物,因为所述GIP激动剂提供长的终末半衰期。因此,所述GIP类似物可用作代谢紊乱(包括但不限于2型糖尿病、肥胖及相关紊乱)的治疗剂。
本发明在第一方面提供了由通式I表示的GIP类似物,或其可药用盐或溶剂合物,
R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R2 (I)
其中
R1是H-、Ac或pGlu焦谷氨酸(pGlu;(S)-(-)-2-吡咯烷酮-5-羧酸)、C1-4烷基、乙酰基、甲酰基、苯甲酰基和三氟乙酰基,
X2是Aib、Ala、D-Ala、Gly、Ser、N-Me-Ser、Ac3c、Ac4c或Ac5c;
X10是Tyr、Leu或Ser;
X11是Ser或Leu;
X12是Lys、Ψ或Ile;
X15是Asp或Glu;
X16是Ser、Glu、Lys或Ψ;
X17是Ile、Lys、Gln、Arg或Ψ;
X18是His、Arg或Ala;
X19是Gln、Lys、Ala或Glu;
X20是Gln、Lys、Ala、His或Arg;
X21是Ala、Leu、Asp或Glu;
X23是Val或Ile;
X24是Asn或Glu;
X25是Tyr或Trp;
X27是Leu、Glu、Ser、Lys或Val;
X28是Ala、Ser或Arg;
X29是Aib、Gly、Ala、Gln、Thr、Ser或Lys或不存在;
Y1是
Lys-Gly,Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,Gly-Pro-Ser-Ser-Gly-Aa-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln或不存在;
Y2是Ψ或不存在;
R2是-NH2或-OH;
其中Ψ是独立地选自Lys、Arg、Orn和Cys的残基,并且其中所述残基的侧链与亲脂性取代基缀合;
并且其中所述GIP类似物包含一个且仅包含一个残基ψ。
在一个方面,R1是H-、Ac或pGlu。
可存在于式I的一些可变位置处的残基组合包括:
Aib2,Asp15,Lys20;
Aib2,Asp15,Arg20;
Aib2,Asp15,Arg20,Ile23;
Aib2,Ile12,Asp15,Arg20,Ile23,Glu24;
Ile12,Asp15,Ile23;
Ile12,Asp15,Ile23,Glu24;
Ile12,Asp15,Ala21,Ile23;
Aib2,Ala21,Ile23,Glu24;
Aib2,Asp15,Ile23;
Aib2,Asp15,Arg20,Ile23,Gln29;
Aib2,Asp15,Arg20,Gly29;
Aib2,Asp15,Ile17,Arg20,Gly29;
Aib2,Asp15,Ile17,Lys20,Gly29;
DAla2,Asp15,Ile23;
DAla2,Asp15,Ile23,Ala28;
Aib2,Asp15,Ile17,Lys20,Ala28;
Asp15,Ile23,Glu24;
N-Me-Ser2,Asp15,Lys20;
N-Me-Ser2,Asp15,Arg20;
N-Me-Ser2,Asp15,Arg20,Ile23;
N-Me-Ser2,Ile12,Asp15,Arg20,Ile23,Glu24;
N-Me-Ser2,Ala21,Ile23,Glu24;
N-Me-Ser2,Asp15,Ile23;
N-Me-Ser2,Asp15,Arg20,Ile23,Gln29;
N-Me-Ser2,Asp15,Arg20,Gly29;
N-Me-Ser2,Asp15,Ile17,Arg20,Gly29;
N-Me-Ser2,Asp15,Ile17,Lys20,Gly29;
N-Me-Ser2,Asp15,Ile23;
N-Me-Ser2,Asp15,Ile23,Ala28;
Ac3c2,Asp15,Lys20;
Ac3c2,Asp15,Arg20;
Ac3c2,Asp15,Arg20,Ile23;
Ac3c2,Ile12,Asp15,Arg20,Ile23,Glu24;
Ac3c2,Ala21,Ile23,Glu24;
Ac3c2,Asp15,Ile23;
Ac3c2,Asp15,Arg20,Ile23,Gln29;
Ac3c2,Asp15,Arg20,Gly29;
Ac3c2,Asp15,Ile17,Arg20,Gly29;
Ac3c2,Asp15,Ile17,Lys20,Gly29;
Ac3c2,Asp15,Ile23;
Ac3c2,Asp15,Ile23,Ala28;
Ac4c2,Asp15,Lys20;
Ac4c2,Asp15,Arg20;
Ac4c2,Asp15,Arg20,Ile23;
Ac4c2,Ile12,Asp15,Arg20,Ile23,Glu24;
Ac4c2,Ala21,Ile23,Glu24;
Ac4c2,Asp15,Ile23;
Ac4c2,Asp15,Arg20,Ile23,Gln29;
Ac4c2,Asp15,Arg20,Gly29;
Ac4c2,Asp15,Ile17,Arg20,Gly29;
Ac4c2,Asp15,Ile17,Lys20,Gly29;
Ac4c2,Asp15,Ile23;
Ac4c2,Asp15,Ile23,Ala28;
Ac5c2,Asp15,Lys20;
Ac5c2,Asp15,Arg20;
Ac5c2,Asp15,Arg20,Ile23;
Ac5c2,Ile12,Asp15,Arg20,Ile23,Glu24;
Ac5c2,Ala21,Ile23,Glu24;
Ac5c2,Asp15,Ile23;
Ac5c2,Asp15,Arg20,Ile23,Gln29;
Ac5c2,Asp15,Arg20,Gly29;
Ac5c2,Asp15,Ile17,Arg20,Gly29;
Ac5c2,Asp15,Ile17,Lys20,Gly29;
Ac5c2,Asp15,Ile23;或Ac5c2,Asp15,Ile23,Ala28。
本发明在另一方面提供了由通式II表示的GIP类似物,或其可药用盐或溶剂合物,
R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R2 (II)
其中
R1是H-、Ac或pGlu;
X2是Aib、Ala、D-Ala或Gly;
X12是Lys、Ψ或Ile;
X15是Asp或Glu;
X16是Ser、Glu、Lys或Ψ;
X17是Ile、Lys、Gln、Arg或Ψ;
X18是His、Arg或Ala;
X19是Gln或Ala;
X20是Gln、Lys、Ala、His或Arg;
X21是Ala、Asp或Glu;
X23是Ile或Val;
X24是Asn或Glu;
X25是Tyr或Trp;
X27是Leu、Glu、Ser、Lys或Val;
X28是Ala、Ser或Arg;
X29是Aib、Gly、Ala、Gln、Thr、Ser或Lys或不存在;
Y1是
Lys-Gly,Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-,Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln或不存在;
Y2是Ψ或不存在;
R2是-NH2或-OH;
其中Ψ是Lys残基,其中所述Lys残基的侧链与亲脂性取代基缀合;
并且其中所述GIP类似物包含一个且仅包含一个残基ψ。
可存在于式II的一些可变位置处的残基组合包括:
Aib2,Lys12,Asp15,Lys20;
Aib2,Lys12,Asp15,Arg20;
Aib2,Asp15,Arg20;
Alib2,Ile12,Asp15,Arg20,Glu24;
Ile12,Asp15,Ile23;
Ile12,Asp15,Glu24;
Ile12,Asp15,Ala21;
Aib2,Lys12,Ala21,Glu24;
Aib2,Lys12,Asp15;
Aib2,Lys,12,Asp15,Arg20,Gln29;
Aib2,Lys,12,Asp15,Arg20,Gly29;
Aib2,Lys12,Asp15,Ile17,Arg20,Gly29;
Aib2,Asp15,Ile17,Lys20,Gly29;
DAla2,Asp15;
DAla2,Asp15,Ala28;
Aib2,Asp15,Ile17,Lys20,Ala28;
Asp15,Glu24;
Ala2,Lys12,Asp15,Lys20;
Ala2,Lys12,Asp15,Arg20;
Ala2,Asp15,Arg20;
Ala2,Ile12,Asp15,Arg20,Glu24;
Ala2,Ile12,Asp15,Ile23;
Ala2,Ile12,Asp15,Glu24;
Ala2,Ile12,Asp15,Ala21;
Ala2,Lys12,Ala21,Glu24;
Ala2,lys12,Asp15;
Ala2,Lys12,Asp15,Arg20,Gln29;
Ala2,Lys12,Asp15,Arg20,Gly29;
Ala2,Lys12,Asp15,Ile17,Arg20,Gly29;
Ala2,Asp15,Ile17,Lys20,Gly29;
Ala2,Asp15;
Ala2,Asp15,Ala28;
Ala2,Asp15,Ile17,Lys20,Ala28;
Gly2,Lys12,Asp15,Lys20;
Gly2,Lys12,Asp15,Arg20;
Gly2,Asp15,Arg20;
Gly2,Ile12,Asp15,Arg20,Glu24;
Gly2,Ile12,Asp15,Ile23;
Gly2,Ile12,Asp15,Glu24;
Gly2,Ile12,Asp15,Ala21;
Gly2,Lys12,Ala21,Glu24;
Gly2,Lys12,Asp15;
Gly2,Lys12,Asp15,Arg20,Gln29;
Gly2,Lys12,Asp15,Arg20,Gly29;
Gly2,Lys12,Asp15,Ile17,Arg20,Gly29;
Gly2,Asp15,Ile17,Lys20,Gly29;
Gly2,Asp15;
Gly2,Asp15,Ala28;
Gly2,Asp15,Ile17,Lys20,Ala28;或
Gly2,Asp15,Glu24,
本发明在另一方面提供了由通式III表示的GIP类似物,或其可药用盐或溶剂合物,
R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y1-Y2-R2 (III)
其中
R1是H-、Ac或pGlu;
X15是Asp或Glu;
X16是Lys或Ψ;
X17是Ile或Ψ;
X18是His或Ala;
X19是Gln或Ala;
X20是Gln、Lys或Arg;
X21是Ala、Asp或Glu;
X24是Asn或Glu;
X25是Tyr或Trp;
X28是Ala、Ser或Arg;
X29是Gln或不存在;
Y1是Lys-Gly,Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln或不存在;
Y2是Ψ或不存在;
R2是-NH2或-OH;
其中Ψ是独立地选自Lys、Arg、Orn和Cys的残基,并且其中所述残基的侧链与亲脂性取代基缀合;
并且其中所述GIP类似物包含一个且仅包含一个残基ψ。
可存在于式III的一些可变位置处的残基组合包括:
Asp15,Lys20;
Asp15,Arg20;
Asp15,Arg20,Glu24;
Asp15,Lys16;
Asp15,Lys16,Glu24;
Asp15,ψ16,Ala21;
Ala21,Glu24;
Asp15,Arg20,Gln29;
Asp15,Arg20,Gly29;
Asp15,Ile17,Arg20,Gly29;
Asp15,Ile17,Lys20,Gly29;
Asp15Ala28;
Asp15,Ile17,Lys20,Ala28;
Asp15,Ile23,Glu24;
Asp15,ψ17,Lys20;
Asp15,ψ17,Arg20;
Asp15,ψ17,Arg20
Asp15,ψ17,Arg20,Glu24;
Asp15,Lys16,ψ17;
Asp15,Lys16,ψ17,Glu24;
Asp15,ψ17,Ala21;
Ala21,ψ17,Glu24;
Asp15,Asp15,ψ17,Arg20,Gln29;
Asp15,ψ17,Arg20,Gly29;
Asp15,Ile17,Arg20,Gly29;
Asp15,Ile17,Lys20,Gly29;
Asp15;ψ17;
Asp15,ψ17,Ala28;
Asp15,Ile17,Lys20,Ala28;或
Asp15,ψ17,Ile23,Glu24.
GIP类似物可具有式R1-Z-R2,其中R1和R2如上所定义,并且Z具有以下序列:
Y-Aib-EGTFISDYSIELDKψHQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDψIHQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEKψHQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSψ;
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ;
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQψ;
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKGψ;
Y-Aib-EGTFISDYSIELDKψHQQDFVNYLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKψHQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKψAAQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEKψAAKEFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEKψAQRAFVEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPSΨ;
Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQψ;
Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPSψ;
Y-Aib-EGTFISDYSIELDKKΨAQRAFVEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKKψAAQAFVNWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKψAAQDFVNWLLAAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKψAAQDFINWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKψAAQDFIEWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKψAAQDFIEWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKψIAQRAFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSKψELDKIAQRAFIEWLLAQGPSSGAPPPS;
Y-DAla-EGTFISDYSIELDKKψAQRAFIEWLLAQGPSSGAPPPS;
Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKψ;
Y-Aib-EGTFISDYSIELDKKψAAQDFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKKψAAQDFINWLLAQGPSSGAPPPS.;或
Y-Aib-EGTFISDYSIELDKKψAAQAFIEWLLAQGPSSGAPPPS。
GIP类似物可具有式R1-Z-R2,其中R1和R2如上所定义,并且Z具有以下序列:
Y-Aib-EGTFISDYSIELDK-K(十六烷酰基-异Glu)-HQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELD-K(十六烷酰基-异Glu)-IHQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEK-K(十六烷酰基-异Glu)-HQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(十六烷酰基-异Glu);
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(十六烷酰基-异Glu);
Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(十六烷酰基-异Glu);
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-HQQDFVNYLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-HQQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAKEFVNWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K((1g-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-羰基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQAFVNWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFINWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS;
Y-Aib-EGTFISDYSIELD-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-IAQRAFIEWLLAQGPSSGAPPPS-;
Y-Aib-EGTFISDYS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-ELDKIAQRAFIEWLLAQGPSSGAPPPS;
Y-DAla-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS;
Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3);
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFIEWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFINWLLAQGPSSGAPPPS;
Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS:或
Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS.
GIP类似物可以是:
H-Y-Aib-EGTFISDYSIELDK-K(十六烷酰基-异Glu)-HQQDFVNWLLAQGPSSGAPPPS-NH2(化合物1);
H-Y-Aib-EGTFISDYSIELD-K(十六烷酰基-异Glu)-IHQQDFVNWLLAQGPSSGAPPPS-NH2(化合物2);
H-Y-Aib-EGTFISDYSIELEK-K(十六烷酰基-异Glu)-HQQDFVNWLLAQGPSSGAPPPS-NH2(化合物3);
H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物4);
H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(十六烷酰基-异Glu)-NH2(化合物5);
H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(十六烷酰基-异Glu)-NH2(化合物6);
H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(十六烷酰基-异Glu)-NH2(化合物7);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-HQQDFVNYLLAQGPSSGAPPPS-NH2(化合物8);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-HQQDFVNWLLAQGPSSGAPPPS-NH2(化合物9);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAQGPSSGAPPPS-NH2(化合物10);
H-Y-Aib-EGTFISDYSIELEK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAKEFVNWLLAQGPSSGAPPPS-NH2(化合物11);
H-Y-Aib-EGTFISDYSIELEK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2(化合物12);
H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物13);
H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物14);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAGPSSGAPPPS-NH2(化合物15);
H-Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物16);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFVEWLL-AQGPSSGAPPPS-NH2(化合物17);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH2(化合物18);
H-Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH2(化合物19);
H-Y-Aib-EGTFISDYSIELDK-K((1g-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2(化合物20);
H-Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS-NH2(化合物21);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS-NH2(化合物22);
H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物23);
H-Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物24);
H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物25);
H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-NH2(化合物26);
H-Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物27);
H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-NH2(化合物28);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQAFVNWLLAGPSSGAPPPS-NH2(化合物29);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFVNWLLAAGPSSGAPPPS-NH2(化合物30);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFINWLLAGPSSGAPPPS-NH2(化合物31);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS-NH2(化合物32);
H-Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS-NH2(化合物33);
H-Y-Aib-EGTFISDYSIELD-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-IAQRAFIEWLLAQGPSSGAPPPS-NH2(化合物34);
H-Y-Aib-EGTFISDYS-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-ELDKIAQRAFIEWLLAQGPSSGAPPPS-NH2;;(化合物35);
H-Y-DAla-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH2(化合物36);
H-Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-NH2(化合物37);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFIEWLLAQGPSSGAPPPS-NH2(化合物38);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQDFINWLLAQGPSSGAPPPS-NH2(化合物39);
H-Y-Aib-EGTFISDYSIELDK-K([19-羧基-十九烷酰基]-异Glu-Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2(化合物40);和
或
H-Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2(化合物41)
本发明还提供了药物组合物,其包含与载体(优选可药用载体)混合的如本文所述的GIP类似物或其可药用盐或溶剂合物。GIP类似物可以例如为可药用酸加成盐。
药物组合物可配制成适于通过注射或输注施用的液体。药物组合物可配制成使得所述GIP类似物受控释放,例如缓慢释放。
本发明还提供了包含本文所述的GIP类似物的治疗药盒以及包含本文所述的GIP类似物的装置。
本发明还提供了本文所述的GIP类似物或其可药用盐或溶剂合物,其用于医学治疗的方法,例如用于治疗和/或预防代谢紊乱。
本发明还提供了本文所述的GIP类似物或其可药用盐或溶剂合物在制备用于治疗和/或预防代谢紊乱之药物中的用途。
本发明还提供了预防和/或治疗对象中的代谢紊乱的方法,其包括向所述对象施用本文所述的GIP类似物或其可药用盐或溶剂合物。
代谢紊乱可以是糖尿病或糖尿病相关紊乱,或者肥胖或肥胖相关紊乱。肥胖与糖尿病之间的关联是公知的,因此这些病症可以但并不必须是分开的或相互排斥的。
糖尿病相关紊乱包括胰岛素抵抗、葡萄糖耐受不良、空腹血糖升高、前驱糖尿病、1型糖尿病、2型糖尿病、妊娠期糖尿病高血压、血脂异常及其组合。
糖尿病相关紊乱还包括动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和中风;或者与以下相关的病症:致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态、促炎状态和骨相关紊乱,如骨质疏松症。
血脂紊乱可选自高甘油三酯、低HDL胆固醇、高LDL胆固醇以及动脉壁中斑块堆积或其组合。
血栓前状态可选自血液中高纤维蛋白原水平和血液中高纤溶酶原激活物抑制剂-1水平。
促炎状态可以是血液中C反应蛋白水平升高。
肥胖相关紊乱包括肥胖关联的炎症、肥胖关联的胆囊疾病或肥胖诱发的睡眠呼吸暂停,或者可与选自以下的病症相关:致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态和促炎状态或其组合。
附图简要说明
图1:5小时禁食小鼠的OGTT中的血糖水平(A-C)和血糖曲线下面积(AUC)(D)。在经口强饲葡萄糖(t=0)前4小时,用载剂、GLP-1类似物利拉鲁肽(10nmol/kg)和GIP受体激动剂(化合物12、13、17和21,3-300nmol/kg)皮下(s.c.)注射小鼠。数据为平均值±SEM;n=6。与载剂相比的统计学差异:*p<0.05,**p<0.01,***p<0.001。
图2:5小时禁食小鼠的OGTT中的血糖水平(A-D)和血糖曲线下面积(AUC)(E)。在经口强饲葡萄糖(t=0)前4小时,用载剂和GIP受体激动剂(化合物12、18、41、33和35,3-300nmol/kg)皮下(s.c.)注射小鼠。数据为平均值±SEM;n=6。与载剂相比的统计学差异:***p<0.001。
图3:三周处理期间DIO小鼠的相对体重变化(Δ体重=每个研究日的体重-第1天的体重)。每天用两种单独的皮下注射处理动物1次。第一次注射为用载剂1或GLP-1类似物利拉鲁肽(20nmol/kg)。第二次注射为用载剂2或化合物12(3和30nmol/kg)。GIP激动剂仅在研究的每个第三天(从第1天开始)给药。在其他天,GIP激动剂替换为载剂2。数据为平均值±SEM;n=8-9。在第22天与载剂相比的统计学差异:***p<0.001。利拉鲁肽与利拉鲁肽和GIP激动剂共处理之间的统计学差异(p<0.05)用线表示。
图4:使用载剂、GLP-1类似物利拉鲁肽、利拉鲁肽+化合物10或12(A)、利拉鲁肽+化合物17(B)、利拉鲁肽+化合物18(C)、利拉鲁肽+化合物35(D)或利拉鲁肽+化合物41(E)处理四周期间,DIO小鼠的相对体重变化(Δ体重=每个研究日的体重-第0天的体重)。每天用两种单独的皮下注射处理动物一次。第一次注射为用载剂1或利拉鲁肽(20nmol/kg)。第二次注射为用载剂2或GIP激动剂(30和/或300nmol/kg)。GIP激动剂仅在研究的每个第三天(从第0天开始)给药。在其他天,GIP激动剂替换为载剂2。数据为平均值±SEM;n=9。在第27天与载剂相比的统计学差异:***p<0.001。利拉鲁肽与利拉鲁肽和GIP激动剂共处理之间的统计学差异(p<0.05)用线表示。
发明详述
除非本文另有定义,否则本申请中所使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。通常,本文所述的与化学、分子生物学、细胞和癌症生物学、免疫学、微生物学、药理学以及蛋白质和核酸化学关联使用的术语和技术是本领域中公知和常用的。
定义
除非另有说明,否则对于在以上书面描述中所使用的特定术语给出如下定义。
在整个本说明书中,词语“包含”或其变化形式将理解为暗示包含所述整体(或组分)或整体(或组分)的组,但不排除任何其他整体(或组分)或整体(或组分)的组。
除非上下文另有明确说明,否则没有数量词修饰的对象包括多个所述对象。
术语“包括”用于表示“包括但不限于”。“包括”和“包括但不限于”可互换使用。
术语“患者”、“对象”和“个体”可互换使用并且是指人或非人动物。这些术语包括哺乳动物如人;灵长动物;家畜动物(例如牛、猪);伴侣动物(例如犬、猫)和啮齿类动物(例如小鼠和大鼠)。
在本发明的上下文中的术语“溶剂合物”是指在溶质(这里指的是根据本发明的肽缀合物或其可药用盐)与溶剂之间形成的确定化学计量的复合物。在这一点上,所述溶剂可以例如是水、乙醇或其他可药用的代表性小分子有机物,例如但不限于乙酸或乳酸。当上述溶剂是水时,这样的溶剂合物通常被称为水合物。
本发明上下文中使用的术语“激动剂”是指通过所讨论的受体类型活化信号传导的物质(配体)。本发明上下文中使用的术语“拮抗剂”是指通过所讨论的受体类型减少信号传导的物质(配体)。
在整个说明书和权利要求书中,使用天然(或“蛋白质的(proteinogenic)”)氨基酸的常规单字母和三字母代码,以及其他(非天然或“非蛋白质的(non-proteinogenic)”)α-氨基酸的普遍接受的三字母代码,例如,Aib(α-氨基异丁酸)、Orn(鸟氨酸)和D-Ala(D-丙氨酸)。除非明确指出,否则本发明的肽中的所有氨基酸残基优选为L构型。
本文中所公开的序列是在序列的氨基端(N端)处并入“H-”部分的序列,以及在序列的羧基端(C端)处并入“-OH”部分或“-NH2”部分的序列。在这样的情况下,除非另有说明,否则所述序列的N端处的“H-”部分表示氢原子(即R1=H),对应于在N端处存在游离的伯氨基或仲氨基,而在所述序列的C端处的“-OH”或“-NH2”部分(即R2=OH或NH2)分别表示C端处的羧基(COOH)或酰胺基(CONH2)。
本发明的化合物具有GIP生物活性,特别是在代谢疾病例如糖尿病和肥胖的治疗中。这可在例如体内测定中进行评估,其中在测试动物已经用GIP类似物治疗或暴露于GIP类似物之后测定血糖水平或另外的生物活性。当将本发明的化合物与GLP-1受体激动剂一起施用于糖尿病患者和/或超重或肥胖对象时,其可特别有效地改善血糖控制(glycaemiccontrol)并减轻体重。当按照相当的给药方案给药时,这种组合治疗获得的效果可优于在相当对象中单独施用GLP-1受体激动剂所获得的效果。本发明的化合物在单独施用时还能够改善血糖控制和减轻体重。Y1和Y2基团对GIP类似物具有稳定作用。不受任何理论的约束,认为包含exendin-4的C末端部分和GIP化合物的基团对肽的折叠有影响。在糖尿病对象或超重对象的治疗中,当按照相当的给药方案给药时,用本发明的GIP类似物的治疗效果可优于在相当对象中用等同量(以质量或摩尔比计)野生型人GIP获得的效果,无论单独还是与另一种抗糖尿病药剂或抗肥胖药剂组合。
体外测定中的活性也可用作化合物活性的量度。
通常,所述化合物对GIP受体(称为GIP-R)具有活性(即,激动剂活性)。EC50值可用作激动剂对给定受体效力的数值量度。EC50值是在特定测定中实现化合物最大活性一半时所需的化合物浓度的测量值。在任何给定的测定中,可相对于人GIP的EC50评估给定测定中化合物的EC50值。因此,在人GIP受体的情况下,测试化合物的EC50值与野生型人GIP的EC50的比率(EC50[测试化合物]/EC50[GIP])可小于10、小于5、小于1、小于0.1、小于0.05或小于0.01。EC50值可使用下文实施例中描述的人GIP受体测定法来测定。在这种测定中,化合物的EC50值可以为例如0.001-0.050nM、0.001-0.030nM、0.001-0.020nM或0.001-0.010nM。
在GLP-1受体的情况下,化合物通常具有最小激动剂活性或不具有激动剂活性。例如,人GIP受体的情况下,测试化合物的EC50值与GLP-1激动剂Exendin-4的EC50值的比率(EC50[测试化合物]/EC50[Ex4])可以为至少约100、至少约250、至少约500、至少约750、至少约1000、至少约5000或至少约10,000。(此处使用“约”表示+/-10%)。EC50值可以使用以下实施例中描述的人GLP-1受体测定法来测定。在这种测定中,化合物的EC50值可以例如为至少1nM、至少3nM、至少5nM或至少10nM。
亲脂性基团
本发明的化合物包含残基Ψ,即选自Lys、Arg、Orn和Cys的残基,在所述残基中侧链与亲脂性取代基缀合。
不希望受到任何特定理论的约束,认为所述取代基与血流中的血浆蛋白质(例如白蛋白)结合,从而保护本发明化合物不被酶促降解,并因此提高所述化合物的半衰期。所述取代基还可调节所述化合物例如对GIP受体的效力。
取代基在侧链的远离α-碳的末端处与官能团缀合。因此,通过存在所述取代基,可降低或完全消除Lys、Arg、Orn或Cys侧链参与由官能团介导的相互作用(例如,分子内和分子间相互作用)的正常能力。因此,所述化合物的总体性质可对实际作为残基Ψ存在的氨基酸变化相对不敏感。因此,认为任何残基Lys、Arg、Orn和Cys可存在于其中允许Ψ的任何位置。然而,在某些实施方案中,Ψ的氨基酸组分为Lys可能是有利的。
因此,Ψ为Lys、Arg、Orn或Cys残基,在所述残基中侧链与具有式-Z1或-Z2-Z1的取代基缀合。
-Z1是在末端以-X-与Ψ或Z2连接的脂肪链;
其中
-X-是键、-CO-、-SO-或-SO2-;
以及,任选地,Z1在链远离连接-X-的末端处具有极性基团;所述极性基团包括羧酸或羧酸生物电子等排体、膦酸或磺酸基团;
并且其中-Z2-(如果存在的话)是将Z1与Ψ相连的下式的间隔物:
其中:
每个Y独立地为-NH、-NR、-S或-O,其中R是烷基、保护基团或者与间隔物Z2的另一部分形成键;
每个X独立地为键、CO-、SO-或SO2-;
前提条件是当Y是-S时,与其结合的X是键;
每个V独立地为连接Y和X的二价有机部分;
并且n是1至10。
基团Z1
Z1是具有与Ψ或与Z2之连接(在本文中称为-X-)的脂肪链。-X-可以是例如键、酰基(-CO-)、亚磺酰基(-SO-)或磺酰基(-SO2-)。当Z1与Ψ直接结合时,即,当Z2不存在时,优选地,-X-是酰基(-CO-)、亚磺酰基(-SO-)或磺酰基(-SO2-)。最优选地,-X-是酰基(-CO-)。
Z1还可具有极性基团,所述极性基团位于链远离连接-X-的末端处。换句话说,所述连接相对于所述极性基团位于ω位置。所述极性基团可直接与脂肪链的末端结合,或者可以通过接头结合。
优选地,所述极性基团是酸性或弱酸性基团,例如,羧酸或羧酸生物电子等排体、膦酸盐/酯或磺酸盐/酯。所述极性基团在水中的pKa可为-2至12,更优选1至7,更优选3至6。某些优选的极性基团的pKa为4至5。
例如,但并不限于,所述极性基团可包括羧酸(-COOH)或羧酸生物电子等排体、膦酸(-P(O)(OH)2)或磺酸(-SO2OH)基团。
优选地,所述极性基团(如果存在的话)包括羧酸或羧酸生物电子等排体。合适的羧酸生物电子等排体是本领域中已知的。优选地,所述生物电子等排体具有pKa与相应羧酸相似的质子。合适的生物电子等排体的实例可以包括但不限于四唑、酰基磺酰胺、酰基羟胺和方酸衍生物,如下所示(---表示连接点):
R是例如Me、CF3
本文中所使用的脂肪链是指包含碳原子链的部分,所述碳原子主要被氢或类氢原子(例如烃链)取代。这样的脂肪链通常被称为是亲脂性的,尽管可以理解取代可能改变整个分子的亲脂性。
所述脂肪链可以是脂肪族的。其可以是完全饱和的或者可包含一个或更多个双键或三键。每个双键(如果存在的话)可以是E或Z构型。所述脂肪链在其长度上也可具有一个或更多个环亚烷基或杂环亚烷基部分,并且另外地或者替代地在其长度上可具有一个或更多个亚芳基或杂亚芳基部分。例如,所述脂肪链可在其长度上并入例如如下所示的亚苯基或亚哌嗪基部分(其中---表示链内的连接点)。
所述脂肪链可以衍生自脂肪酸,例如,其可衍生自具有6至12个碳原子的脂肪族尾的中链脂肪酸(medium-chain fatty acid,MCFA);具有13至21个碳原子的脂肪族尾的长链脂肪酸(long-chain fatty acid,LCFA);或具有22或更多个碳原子的脂肪族尾的非常长链脂肪酸(LCFA)。线性饱和脂肪酸的实例包括十三(十三烷)酸、肉豆蔻(十四烷)酸、十五烷(十五烷)酸、棕榈(十六烷)酸和十七(十七烷)酸,从所述线性饱和脂肪酸可以得到合适的脂肪链。线性不饱和脂肪酸的实例包括肉豆蔻油酸、棕榈油酸、杉皮酸(sapietic acid)和油酸,从所述线性不饱和脂肪酸可以得到合适的脂肪链。
所述脂肪链可通过酰胺键、亚磺酰胺键、磺酰胺键,或者通过酯键,或者通过醚、硫醚或胺键与Ψ或与Z2连接。因此,所述脂肪链可具有至Ψ或至Z2的键或者酰基(-CO-)、亚磺酰基(-SO-)或磺酰基(-SO2-)基团。优选地,所述脂肪链具有含有酰基(-CO-)的末端,并通过酰胺或酯键与Ψ或Z2连接。
在一些实施方案中,Z1为下式的基团:
A-B-Alk-X-
其中
A是氢或羧酸、羧酸生物电子等排体、膦酸或磺酸基;
B是键或接头;
X是键、酰基(-CO-)、亚磺酰基(-SO-)或磺酰基(-SO2-);并且
Alk是可任选地被一个或更多个取代基取代的脂肪链。所述脂肪链的长度优选是6至28个碳原子(例如,C6-28亚烷基),更优选地,长度是12至26个碳(例如,C12-26亚烷基),更优选地,长度是16至22个碳(例如,C16-22亚烷基),并且可以是饱和或不饱和的。优选地,Alk是饱和的,即,优选Alk为亚烷基。
脂肪链上的任选取代基可独立地选自氟、C1-4烷基,优选甲基;三氟甲基、羟甲基、氨基、羟基、C1-4烷氧基,优选甲氧基;氧代和羧基,并且可独立地位于沿着链的任何点。在一些实施方案中,每个任选的取代基选自氟、甲基和羟基。在存在多于一个取代基的情况下,取代基可以相同或不同。优选地,取代基的数目是0至3;更优选地,所述脂肪链是未经取代的。
B可以是键或接头。当B是接头时,其可以是环亚烷基、杂环亚烷基、C6亚芳基或C5-6杂亚芳基、或C6亚芳基-O-或-C5-6杂亚芳基-O-。
当B是亚苯基时,其可以例如选自1,2-亚苯基、1,3-亚苯基、1,4-亚苯基,优选1,4-亚苯基(使得A-B-是4-苯甲酸取代基或4-苯甲酸生物电子等排体)。当B是亚苯基-O-时,其可以例如选自1,2-亚苯基-O-、1,3-亚苯基-O-、1,4-亚苯基-O-,优选1,4-亚苯基-O。B的每个亚苯基可以任选地被选自以下的一个或更多个取代基取代:氟、甲基、三氟甲基、氨基、羟基、和C1-4烷氧基,优选甲氧基。应当理解,可以选择取代基种类(identity)和位置以精细地改变极性基团的pKa。合适地诱导的(inductively)或内消旋的(mesomerically)吸电子或供电子基团及其位置效应是本领域中已知的。在一些实施方案中,B可以是C5-6杂亚芳基,例如,亚吡啶基或亚噻吩基,并且可如描述的任选地被取代。
例如,在一些实施方案中,A-B-可以选自:
优选地,A为H或HOOC-,并且B为键。
应当理解,当A为氢时,B是键且Alk是未经取代的亚烷基,A-B-Alk-为式H3C-(CH2)n-的烷基链。
在一些实施方案中,Z1为下式的酰基:
A-B-Alk-(CO)-
或下式的磺酰基:
A-B-Alk-(SO2)-。
优选地,Z1为下式的酰基:
A-B-亚烷基-(CO)-
其中A和B如以上所定义的。
在一些实施方案中,A是-COOH且B是键。因此,某些优选的Z1来源于式HOOC-(CH2)12-22-COOH的长链饱和α,ω-二羧酸,优选在脂肪链中具有偶数个碳原子的长链饱和α,ω-二羧酸。在另一些实施方案中,A是H且B是键。因此,某些优选的Z1来源于式HOOC-(CH2)12-22-CH3的长链饱和羧酸,优选在脂肪链中具有偶数个碳原子的长链饱和羧酸。
例如,但不限于,Z1可以是:
A-B-C16-20亚烷基-(CO)-,其中A为H或-COOH且B为键,例如:
17-羧基-十七烷酰基HOOC-(CH2)16-(CO)-;
19-羧基-十九烷酰基HOOC-(CH2)18-(CO)-;
十八烷酰基H3C-(CH2)16-(CO)-;
二十烷酰基H3C-(CH2)18-(CO)-;
羧酸基团(如果存在的话)可被如本文所详述的生物电子等排体替换。
基团Z2
Z2是任选的间隔物,其将Z1与Ψ的氨基酸组分的侧链进行连接。最通常而言,Z2(如果存在的话)是在一端结合Y而在另一端结合X的间隔物,所述Y可以是氮、氧或硫原子,所述X可以是键或酰基(-CO-)、亚磺酰基(-SO-)、磺酰基(-SO2-)或不存在。因此,Z2可以是下式(---表示连接点)的间隔物:
其中:
Y可以是-NH、-NR、-S或-O,其中R可以是烷基、保护基团或者可与所述间隔物的另一部分形成键,剩余价键与Z1形成键;
X可以是键、CO-、SO-或SO2-,剩余价键与Ψ的氨基酸组分的侧链的形成键;
V是连接Y和X的二价有机部分;
并且n可以是1、2、3、4、5、6、7、8、9或10。在n是2或更大的情况下,每个Y、V和X独立于每个其余的Y、V和X。
因此,根据Y和X的性质以及Z1和侧链上的相应连接基团,Z2可在每侧通过酰胺、亚磺酰胺、磺酰胺或酯键或通过氨基、醚或硫醚键相结合。在n是2或更大的情况下,每个V也可通过如所描述的键与各个相邻的V结合。优选地,连键是酰胺、酯或磺酰胺,最优选酰胺。因此,在一些实施方案中,每个Y是-NH或-NR且每个X是CO-或SO2-。最优选地,-X-是酰基(-CO-)。
在一些实施方案中,Z2是式-SA-、-SB-、-SA-SB-或-SB-SA-的间隔物,其中SA和SB如下所定义。
在一些实施方案中,Z2选自-SA-或-SB-SA-,即,[侧链]-Z2Z1是[侧链]-SA-Z1或[侧链]-SB-SA-Z1。
基团SA
SA可以是单个氨基酸残基或氨基酸衍生物的残基,特别是在C端处用亚磺酰基或磺酰基代替羧基部分的氨基酸衍生物残基。另外地或替代地,单个氨基酸残基可具有在N端处代替氮原子的氧或硫原子。
SA可以是或可包含含氮杂环,所述含氮杂环在一端通过键、羧基、亚磺酰基或磺酰基,在另一端通过环氮原子结合在亲脂性基团内。例如,SA可包含哌嗪环。
适当地,SA是具有1或2个氮原子并被X基团取代的5至8元杂环,其中X为键、CO-、SO-或SO2-,并且其中L(如果存在的话)是C1-4亚烷基(-表示亲脂性基团内的连接点)。
优选地,SA是具有1或2个(优选2个)氮原子并且被-CH2CO-、-CH2SO-或-CH2SO2-基团取代的6元杂环。
例如,SA可以是:
例如,SA可以是:
优选地,SA是单个氨基酸残基或哌嗪-1-基-乙酰基。更优选地,SA是单个氨基酸残基。
在一些实施方案中,氨基酸可选自γ-Glu、α-Glu、α-Asp、β-Asp、Ala、β-Ala(3-氨基丙酸)、Dapa(2,3-二氨基丙酸)、Dab(2,4-二氨基丁酸)和Gaba(4-氨基丁酸)。应当理解,在存在多于一个羧酸或氨基部分的情况下,只要合适,连接可以在任何部分处。在残基内未结合的任何羧酸或氨基残基可以是游离的,即,作为游离羧酸或伯胺存在,或者可以是衍生化的。合适的衍生化是本领域中已知的。例如,羧酸部分可作为酯(例如作为甲基酯)存在于SA氨基酸残基中。氨基部分可作为烷基化的(例如,甲基化的)胺存在,或者可作为酰胺或氨基甲酸酯部分被保护。其他合适的氨基酸包括β-Ala(3-氨基丙酸)和Gaba(4-氨基丁酸)和类似的ω氨基酸。
应当理解,氨基酸可以是D或L,或外消旋或对映富集的混合物。在一些实施方案中,氨基酸是L-氨基酸。在一些实施方案中,氨基酸是D-氨基酸。
在一些优选的实施方案中,SA具有羧酸取代基,优选γ-Glu、α-Glu、α-Asp和β-Asp及其亚磺酰基和磺酰基衍生物。因此,在一些实施方案中,氨基酸残基是:
其中,-X-是-CO-、-SO-、-SO2-,优选-CO-,并且a是1或2,优选2。在一些实施方案中,羧酸是酯,并且氨基酸残基是:
其中,-X-为-CO-、-SO-、-SO2-,优选-CO-,并且a为1或2,优选2,并且R为C1-4烷基或C6芳基。优选地,R为C1-4烷基,优选甲基或乙基,更优选乙基。
优选的具有羧酸的SA基团是γ-Glu。
优选地,SA选自Dapa或γ-Glu。最优选地,SA为γ-Glu。
基团SB
SB可以是以下通式的接头:
其中PU是聚合单元,并且n是1、2、3、4、5、6、7、8、9或10。连接基团SB的一端是-NH、-NR、-S或-O,其中R可以是烷基、保护基团或者可与所述聚合单元的另一部分形成键;而另一端是键或CO-、SO-或SO2-。因此,根据Y和X的性质以及Z1、SA和Lys上的相应连接基团,每个聚合单元PU可在每侧通过酰胺、亚磺酰胺、磺酰胺或酯键或通过氨基、醚或硫醚键结合。
在一些实施方案中,每个PU可独立地为下式的单元:
其中:
Y可以是-NH、-NR、-S或-O,其中R可以是烷基、保护基团或者可与间隔物的另一部分形成键,剩余价键与Z1形成键;
X可以是键、CO-、SO-或SO2-,剩余价键与Ψ侧链形成键;
并且V是连接Y和X的二价有机部分。
在一些实施方案中,V是天然或非天然氨基酸的α碳,即V是-CHRAA-,其中RAA是氨基酸侧链;或者V是任选取代的C1-6亚烷基,或者V是包含串联的一个或更多个乙二醇单元的链,也称为PEG链,例如,-CH2CH2-(OCH2CH2)m-O-(CH2)p-,其中m是0、1、2、3、4或5,并且p是1、2、3、4或5;当X是CO-时,p优选是1、3、4或5。任选的亚烷基取代基包括氟、甲基、羟基、羟甲基和氨基。
优选的PU单元包括:
(i).单个氨基酸残基:PU i;
(ii).二肽残基:PU ii;以及
(iii).氨基-(PEG)m-羧酸残基:PU iii,
并且可以任意组合或顺序存在。例如,SB可以任意顺序包含每个PU i、PU ii和PU iii中的一个或更多个,或者可仅包含PU i、PU ii和PU iii中的一个或更多个单元,或者选自PU i和PU ii、PU i和PU iii、或PU ii和PU iii的一个或更多个单元。
(i).PU i单个氨基酸残基
每个PU i可独立地选自任何天然或非天然氨基酸残基,并且例如可选自Gly、Pro、Ala、Val、Leu、Ile、Met、Cys、Phe、Tyr、Trp、His、Lys、Arg、Gln、Asn、α-Glu、γ-Glu、Asp、Ser、Thr、Dapa、Gaba、Aib、β-Ala、5-氨基戊酰基、6-氨基己酰基、7-氨基庚酰基、8-氨基辛酰基、9-氨基壬酰基和10-氨基癸酰基。优选地,PU i氨基酸残基选自Gly、Ser、Ala、Thr和Cys,更优选地选自Gly和Ser。
在一些实施方案中,SB是-(PU i)n-,其中n是1至8,更优选5至7,最优选6。在一些优选的实施方案中,SB是-(PU i)n-,n是6,并且每个PU i独立地选自Gly或Ser,优选序列是-Gly-Ser-Gly-Ser-Gly-Gly-。
(ii).PU ii二肽残基
每个PU ii可独立地选自任何二肽残基,所述二肽残基包含通过酰胺键结合的两个天然或非天然氨基酸残基。优选的PU ii二肽残基包括Gly-Gly、Gly-Ser、Ser-Gly、Gly-Ala、Ala-Gly和Ala-Ala,更优选Gly-Ser和Gly-Gly。
在一些实施方案中,SB是-(PU ii)n-,其中n是2至4,更优选3,并且每个PU ii独立地选自Gly-Ser和Gly-Gly。在一些优选的实施方案中,SB是-(PU ii)n-,n是3,并且每个PU ii独立地选自Gly-Ser和Gly-Gly,优选序列是-(Gly-Ser)-(Gly-Ser)-(Gly-Gly)。
在PU i和PU ii内具有立构(stereogenic)中心的氨基酸可以是外消旋的、对映富集的或对映纯的。在一些实施方案中,所述或每个氨基酸独立地为L-氨基酸。在一些实施方案中,所述或每个氨基酸独立地为D-氨基酸。
(iii).PU iii氨基-(PEG)m-羧酸残基
每个PU iii可独立地为以下通式的残基:
其中m为0、1、2、3、4或5,优选1或2,并且p为1、3、4或5,优选1。
在一些实施方案中,m是1且p是1,即,PU iii是8-氨基-3,6-二氧杂辛酸(也称为{2-[2-氨基乙氧基]乙氧基}乙酸和H2N-PEG3-COOH)的残基。该残基在本文中被称为-PEG3-。
其他更长的PEG链也是本领域中已知的。例如,11-氨基-3,6,9-三氧杂十一烷酸(也称为H2N-PEG4-COOH或-PEG4-)。
在一些实施方案中,SB是-(PU iii)n-,其中n是1至3,更优选2。
最优选地,SB是-PEG3-PEG3-。
优选的组合
应理解,上述优选可独立地组合以得到优选的-Z1和-Z2-Z1部分。
一些优选的-Z1和-Z2-Z1部分如下所示(在每种情况下,---表示与Ψ的氨基酸组分侧链的连接点):
(i)[17-羧基-十七烷酰基]-异Glu-Peg3-Peg3
(ii)[17-羧基-十七烷酰基]-异Glu
(iii)十八烷酰基-异Glu-Peg3-Peg3
(iv)二十烷酰基-异Glu-Peg3-Peg3
(v)[19-羧基-十九烷酰基]-异Glu-Peg3-Peg3
(vi)十八烷酰基-Dapa-Peg3-Peg3
(vii)十六烷酰基-异Glu
(viii)(19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3
本领域技术人员清楚地知道用于制备本发明的上下文中使用的化合物的合适技术。合适的化学反应的实例参见例如WO98/08871、WO00/55184、W000/55119、Madsen等(J.Med.Chem.2007,50,6126-32)以及Knudsen等2000(J.Med Chem.43,1664-1669)。
临床应用
本发明上下文中使用的GIP类似物可提供针对代谢疾病的有吸引力的治疗选择,所述代谢疾病包括肥胖、糖尿病、肥胖相关紊乱和糖尿病相关紊乱。当本发明的GIP类似物与GLP-1受体激动剂(作为相同的药物制剂的一部分或作为单独的制剂)组合施用时,其可以特别有效地改善血糖控制和减轻体重。也称为GLP-1受体激动剂或肠促胰岛素模拟物的胰高血糖素样肽-1受体激动剂是GLP-1受体的激动剂。与较早的胰岛素促分泌素(例如磺酰脲类或氯茴苯酸类)相比,其优点之一是降低了引起低血糖的风险。
糖尿病包括以高血糖为特征的一系列代谢疾病,其由胰岛素分泌、胰岛素作用或二者的缺陷引起。根据致病特征将糖尿病分为1型糖尿病、2型糖尿病和妊娠期糖尿病。1型糖尿病占所有糖尿病病例的5-10%,其由分泌胰岛素的胰腺β细胞的自身免疫破坏所导致。糖尿病的急性症状包括:过量尿液的产生、导致补偿性的口渴和增加的流体摄取、视力模糊、无法解释的体重减轻、昏睡以及能量代谢方面的改变。然而,在2型糖尿病中,症状往往不严重或可以不存在。糖尿病的长期高血糖与多种器官的长期损伤、功能失调和障碍有关,尤其是眼、肾、神经、心脏和血管。
2型糖尿病占糖尿病病例的90%至95%,其由一系列复杂的代谢紊乱引起。然而,症状往往不严重或可以不存在。2型糖尿病是内源性胰岛素产生不足以保持血浆糖水平低于诊断阈值的结果。
妊娠期糖尿病是指在怀孕期间鉴定出的任何程度的葡萄糖耐受不良。
前驱糖尿病包括空腹葡萄糖受损和葡萄糖耐量受损,其是指当血糖水平升高但低于确立的糖尿病临床诊断水平时出现的那些状态。
由于另一些代谢风险因素的高度流行,一大部分2型糖尿病和前驱糖尿病患者的发病和死亡风险升高,所述代谢风险因素包括腹部肥胖(腹部内脏周围过多的脂肪组织)、致动脉粥样硬化性血脂异常(血脂紊乱,包括高甘油三酯、低HDL胆固醇和/或高LDL胆固醇,其促使斑块在动脉壁中堆积)、血压升高(高血压)、血栓前状态(例如,血液中高纤维蛋白原或纤溶酶原激活物抑制剂-1)和/或促炎状态(例如,血液中C反应蛋白升高)。
相反地,肥胖导致前驱糖尿病、2型糖尿病以及例如某些类型的癌症、阻塞性睡眠呼吸暂停和胆囊疾病的发病风险升高。血脂异常与心血管疾病的风险升高相关。高密度脂蛋白(HDL)具有临床重要性,原因是血浆HDL浓度与动脉粥样硬化疾病的风险之间存在负相关性。存储在动脉粥样硬化斑块中的大多数胆固醇来源于LDL,因此升高浓度的低密度脂蛋白(LDL)与动脉粥样硬化密切相关。HDL/LDL比是动脉粥样硬化特别是冠状动脉粥样硬化的临床风险指标。
本发明的GIP类似物可用作药剂,用于防止体重增长、促进体重降低、减少过重体重或治疗肥胖(例如,通过控制食欲、进食、食物摄取、卡路里摄入和/或能量消耗和脂类分解),包括病态肥胖以及相关疾病和健康状况,包括但不限于肥胖关联的炎症、肥胖关联的胆囊疾病和肥胖引起的睡眠呼吸暂停。本发明上下文中使用的GIP类似物还可用于治疗胰岛素抵抗、葡萄糖耐受不良、前驱糖尿病、空腹血糖升高、2型糖尿病、高血压、血脂异常(或这些代谢风险因素的组合)、动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和中风。这些是可与肥胖相关的所有病症。然而,在本发明的上下文中使用的化合物的作用可全部或部分地通过对体重的作用来介导,或者可不依赖于对体重的作用。
因此,本发明的GIP类似物可用于治疗和/或预防本文中所述的任何疾病、失调或病症,包括胰岛素抵抗、葡萄糖耐受不良、空腹血糖升高、前驱糖尿病、1型糖尿病、2型糖尿病、妊娠期糖尿病高血压、血脂异常或其组合。在某些实施方案中,糖尿病相关病症选自动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和中风;或者与选自以下的病症有关:致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态和促炎状态或其组合。在某些实施方案中,血脂紊乱选自高甘油三酯、低HDL胆固醇、高LDL胆固醇、动脉壁中斑块堆积或其组合。在某些实施方案中,血栓前状态选自血液中高纤维蛋白原水平和血液中高纤溶酶原激活物抑制剂-1水平。在某些实施方案中,促炎状态是血液中C反应蛋白水平升高。在某些实施方案中,肥胖相关紊乱选自肥胖关联的炎症、肥胖关联的胆囊疾病和肥胖引起的睡眠呼吸暂停。
本发明的GIP类似物还可用于治疗和/或预防与糖尿病相关骨质疏松症(包括提高的骨折风险)有关的任何疾病、失调或病症(Khazai NB等,2009,Current Opinion inEndocrinology,Diabetes and Obesity,第16卷,第6期,435-445)。骨折风险升高可能与骨质受损而不是骨矿物质密度有关。相关机制尚未完全了解,至少部分是由于高血糖、神经病和更高的维生素D缺乏症发生率(Takiishi T等,2010,Endocrinology and MetabolismClinics of North America,第39卷,第2期,419-446)。
在一些实施方案中,本发明还提供包含任选地与可药用载体组合的本发明的GIP类似物(例如GIP激动剂化合物)的治疗药盒。在一些实施方案中,本发明提供了包含本发明的GIP类似物的装置,用于将GIP类似物递送至对象。
药物组合物
本发明的GIP类似物(例如,GIP激动剂化合物)或其盐或溶剂合物可配制成用于储存或施用的药物组合物,其通常在可药用载体中包含治疗有效量的本发明上下文中所使用的化合物或其盐或溶剂合物。在一些实施方案中,所述药物组合物被配制成适合于通过注射或输注施用的液体,或配制成引起GIP类似物的缓慢释放。
本发明化合物的治疗有效量会取决于例如施用途径、接受治疗的哺乳动物的类型和所考虑的具体哺乳动物的身体特征。决定该量的这些因素及其关系是医药领域技术人员公知的。可调整该量和施用方法以实现最佳效力,并且可取决于医药领域技术人员公知的因素,例如体重、饮食、同时用药情况(concurrent medication)等。人用最适剂量大小和给药方案可参考本发明得到的结果,并且可在适当设计的临床试验中验证。
可通过常规方法确定有效剂量和治疗方案,在实验动物中从低剂量开始,然后在提高剂量的同时监测效果,并且还***地改变给药方案。在确定针对给定对象的最佳剂量时,临床医生可考虑多种因素。这样的考虑是本领域技术人员已知的。术语“可药用载体”包括任何标准药用载体。用于治疗用途的可药用载体是制药领域中公知的,并描述于例如Remington′s Pharmaceutical Sciences,Mack Publishing Co.(A.R.Gennaro编著.1985)中。例如,可使用弱酸性或生理pH下的无菌盐水和磷酸盐缓冲盐水。合适的pH缓冲剂可以是例如磷酸盐、柠檬酸盐、醋酸盐、乳酸盐、马来酸盐、三(羟甲基)氨基甲烷(TRIS)、N-三(羟甲基)甲基-3-氨基丙磺酸(TAPS)、碳酸氢铵、二乙醇胺、组氨酸(其在某些实施方案中是优选的缓冲剂)、精氨酸、赖氨酸和醋酸盐,或其混合物。该术语还涵盖在美国药典中列出的用于动物(包括人)的任何试剂。
术语“可药用盐”是指所述化合物的盐。盐包括可药用盐,例如酸加成盐和碱式盐。酸加成盐的实例包括盐酸盐、柠檬酸盐和醋酸盐。碱式盐的实例包括其中阳离子选自碱金属(例如钠和钾)、碱土金属(例如钙)和铵离子+N(R3)3(R4)的盐,其中R3和R4独立地表示任选取代的C1-6烷基、任选取代的C2-6烯基、任选取代的芳基或任选取代的杂芳基。可药用盐的其他实例描述于“Remington′s Pharmaceutical Sciences”,第17版.Alfonso R.Gennaro(编著),Mark Publishing Company,Easton,PA,U.S.A.,1985及更新的版本中,以及Encyclopaedia of Pharmaceutical Technology中。
“治疗”是指用于获得有益或期望的临床结果的方法。出于本发明的目的,有益或期望的临床结果包括但不限于症状缓解、疾病程度减轻、疾病状态稳定(即,不恶化)、疾病发展延后或减缓、疾病状态改善或减轻以及(部分地或全部地)消除(remission),无论是可检测还是不可检测的。“治疗”还可指与未接受治疗时的预期存活相比延长存活期。“治疗”是以防止疾病发生或改变疾病的病理状况为目的而进行的介入。因此,在某些实施方案中,“治疗”指治疗性治疗以及预防或防护性手段二者。需要治疗的对象包括已患病的对象和待预防疾病发生的对象。“治疗”是指与未治疗相比抑制或减轻病理状况或症状(例如,体重增长、高血糖)的升高,并不必然暗示相关病症的完全终止。
本发明的药物组合物可以是单位剂量形式。在这样的形式中,组合物被分成包含合适量活性组分的单位剂量。单位剂量形式可以是包装的制剂,所述包装包含离散量的制剂,例如盒装片剂、胶囊剂以及小瓶或安瓿中的粉末。单位剂量形式本身还可以是胶囊剂、扁囊剂(cachet)或片剂,或可以是合适数量的任何这些包装形式。其可以单剂量可注射形式提供,例如采用注射笔(pen)的形式。可将组合物配制成适于任何合适的施用途径和方式。可药用载体或稀释剂包括适合于经口、经直肠、经鼻或肠胃外(包括皮下、肌内、静脉内、皮内和经皮)施用的制剂中使用的那些。可方便地将所述制剂以单位剂量形式提供,并且可通过药学领域中公知的任何方法来制备。皮下或经皮施用方式可特别适合于本文中所述的某些化合物。
组合疗法
在某些实施方案中,本发明上下文中使用的GIP类似物可作为组合疗法的一部分与至少一种用于治疗糖尿病、肥胖、血脂异常或高血压的其他药剂一起施用。
在这样的情况下,至少两种活性剂可同时施用或分开施用,并作为相同药物制剂的一部分或作为单独的制剂。因此,本发明上下文中使用的GIP类似物(或其盐或溶剂合物)可与抗糖尿病药剂组合使用,所述抗糖尿病药剂包括但不限于:胰高血糖素样肽受体1激动剂、二甲双胍、磺酰脲类、格列奈类(glinide)、DPP-IV抑制剂、格列酮或胰岛素。在某些实施方案中,所述化合物或其盐或溶剂合物与胰岛素、DPP-IV抑制剂、磺酰脲类或二甲双胍(特别是磺酰脲类或二甲双胍)组合使用,以实现充分的血糖控制。在某些优选的实施方案中,所述化合物或其盐或溶剂合物与胰岛素或胰岛素类似物组合使用以实现充分的血糖控制。胰岛素类似物的实例包括但不限于Actraphane和
在某些实施方案中,所述GIP类似物或其盐或溶剂合物还可与一种或更多种抗肥胖药剂组合使用,所述抗肥胖药剂包括但不限于胰高血糖素样肽受体1激动剂、肽YY或其类似物、***素受体1拮抗剂、脂肪酶抑制剂、黑皮质素受体4激动剂或黑色素浓集激素受体1拮抗剂。
在某些实施方案中,所述GIP类似物或其盐或溶剂合物可与抗高血压剂组合使用,所述抗高血压剂包括但不限于血管紧张素转化酶抑制剂、血管紧张素II受体阻断剂、利尿剂、β阻断剂或钙通道阻断剂。
在某些实施方案中,所述GIP类似物或其盐还可与抗血脂异常剂组合使用,所述抗血脂异常剂包括但不限于他汀类、贝特类(fibrate)、烟酸类和/或胆固醇吸收抑制剂。
本发明化合物的合成
核酸分子可以编码式I至III中任一项的氨基酸序列或其前体。编码的氨基酸序列可被认为是本发明化合物的前体。
通常,这样的核酸序列会作为表达构建体提供,其中所述编码核酸与合适的控制序列功能性地连接以指导其表达。所述表达构建体可在能够表达(以及任选地还分泌)所述氨基酸前体的宿主细胞的环境中或在无细胞表达***中提供。
本发明提供了生产本发明GIP类似物的方法,所述方法包括表达所述GIP类似物的氨基酸前体并对所述前体进行修饰以提供GIP类似物。所述修饰可包括对存在于第17位处的Lys、Arg或Cys残基进行化学修饰以引入亲脂性部分,N端或C端的修饰,和/或分子中任何其他氨基酸侧链的修饰(例如,以引入非天然存在的氨基酸残基)。
本发明的化合物也可如下制备:通过标准肽合成方法,例如,通过标准固相或液相方法;逐步或通过片段组装,并分离和纯化最终的肽化合物产物,或者通过重组和合成方法的任意组合。
可优选通过固相或液相肽合成方法来合成本发明的肽化合物。关于这点,可参考WO 98/11125或尤其是Fields,G.B.等,“Principles and Practice of Solid-PhasePeptide Synthesis”;在Synthetic Peptides中,Gregory A.Grant(编辑),OxfordUniversity出版社(第二版,2002)以及本文中的合成实施例。
实施例
以下实施例说明了本发明的某些实施方案。然而,应当理解,这些实施例不意味着也不旨在完全限定本发明的条件和范围。这些实施例是使用标准技术来实施的,除非另外详细说明,否则所述标准技术是本领域技术人员公知和常规的技术。以下实施例仅用于说明目的,并且不应以任何方式解释为限制本发明的范围。
公开了呈现信号传导选择性的GIP类似物以及用于筛选这些化合物的方法。信号传导选择性可以是例如优选通路活化或优选通路抑制,或者二者皆有。单独施用或与GLP-1激动剂组合施用所述类似物可用于治疗和/或预防因体重过重导致的或以体重过重为特征的疾病或病症,包括但不限于:肥胖、病态肥胖、肥胖关联的炎症、肥胖关联的胆囊疾病、肥胖诱发的睡眠呼吸暂停、代谢综合征、前驱糖尿病、胰岛素抵抗、葡萄糖耐受不良、2型糖尿病、1型糖尿病、高血压、致动脉粥样硬化性血脂异常、动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和中风或微血管疾病。
尽管已经以示例的方式描述了本发明的一些实施方案,但明显的是,在本领域技术人员的能力范围内,可在实践中对本发明进行许多不同的修改、变化和改造,以及使用许多等同或替选的方案,其并不偏离本发明的精神或超出权利要求的范围。
本文中参考的所有出版物、专利和专利申请在此以相同程度通过引用整体并入本文,如同每个单独的出版物、专利或专利申请具体和单独地表明通过引用以其整体并入本文一样。
除非另外清楚指明,否则本发明中所使用的方法描述如下。
实施例1
酰化GIP类似物的一般合成
使用标准Fmoc化学在CEM Liberty肽合成仪上进行了固相肽合成。在使用之前将TentaGel S Ram树脂(1g;0.25mmol/g)在NMP(10ml)中溶胀,并使用DCM和NMP在管和反应器之间转移。
偶联
向CEM Discover微波装置中的树脂中添加DMF/DCM(2:1;0.2M;5ml)中的Fmoc-氨基酸以及HATU/DMF或COMU/DMF(0.5M;2ml)和DIPEA-DMF/DCM(2:1)(2.0M;1mI)。将所述偶联混合物加热至75℃持续5分钟,同时用氮气鼓泡通过所述混合物。然后用DMF(4×10ml)洗涤树脂。
去保护
将哌啶/DMF(20%;10ml)添加到树脂中用于初始去保护,并通过微波加热(30秒;40℃)混合物。将反应器排干,并且添加第二部分的哌啶/NMP(20%;10ml)并再次加热(75℃;3分钟)。然后用DMF洗涤(6×10ml)树脂。
侧链酰化
将Fmoc-Lys(ivDde)-OH或替代地具有正交侧链保护基团的另一种氨基酸引入到酰化位置。然后在最后的偶联中使用Boc2O或者替代地通过使用Boc-保护的氨基酸来Boc-保护肽骨架的N端。当肽仍与树脂相连时,使用在NMP中新鲜制备的水合肼(2-4%)选择性地切割所述正交侧链保护基团2×15分钟。未保护的赖氨酸侧链首先与Fmoc-Glu-OtBu或另一个间隔氨基酸偶联,其随后使用如上所述的肽偶联方法用哌啶去保护并用亲脂性部分酰化。
所使用的缩写如下:
COMU:1-[(1-(氰基-2-乙氧基-2-氧代亚乙基氨基氧基)-二甲基氨基-吗
啉代亚甲基)]甲铵六氟磷酸盐
ivDde:1-(4,4-二甲基-2,6-二氧代亚环己基)3-甲基-丁基
Dde:1-(4,4-二甲基-2,6-二氧代亚环己基)-乙基
DCM:二氯甲烷
DMF:N,N-二甲基甲酰胺
DIPEA:二异丙基乙胺
EtOH:乙醇
Et2O:***
HATU:N-[(二甲氨基)-1H-1,2,3-***[4,5-b]吡啶-1-基亚甲基]-N-甲基甲铵六氟磷酸盐N-氧化物
MeCN:乙腈
NMP:N-甲基吡咯烷酮
TFA:三氟乙酸
TIS:三异丙基硅烷。
切割
将树脂用EtOH(3×10ml)和Et2O(3×10ml)洗涤并在室温(r.t.)下干燥至恒重。通过用TFA/TIS/水(95/2.5/2.5;40ml,2小时;r.t.)处理将粗制肽从树脂上切割下来。在减压下除去大部分的TFA,使粗制肽沉淀并用***洗涤三次,并在室温下干燥至恒重。
粗制肽的HPLC纯化
使用配备有C-18柱(5cm;10μm)和级分收集器的PerSeptive Biosystems VISIONWorkstation,用缓冲液A(0.1%TFA,水溶液)和缓冲液B(0.1%TFA,90%MeCN,水溶液)的梯度以35ml/分钟运行,通过制备型反相HPLC将粗制肽纯化至大于90%。通过分析型HPLC和MS分析了级分,将相关级分合并并冻干。最终产物通过HPLC和MS进行表征。
表1示出了合成的化合物。
表1.
化合物9的合成
使用标准Fmoc化学在CEM Liberty肽合成仪上进行固相肽合成。将TentaGel SRam S树脂(1.05g;0.23mmol/g)在使用前在DMF(10ml)中溶胀并且使用DCM和DMF在管和反应器之间转移。
偶联
向CEM Discover微波装置中的树脂中添加DMF/DCM(2:1;0.2M;5ml)中的Fmoc-氨基酸以及COMU/DMF(0.5M;2ml)和DIPEA-DMF/DCM(2:1)(2.0M;1ml)。将所述偶联混合物加热至75℃持续5分钟,同时用氮气鼓泡通过所述混合物。然后用DMF(4×10ml)洗涤树脂。对于从C末端计数的第29和30号氨基酸使用Fmoc-Tyr(OtBu)-Ser(Psi Me,Me)-OH假脯氨酸。将Lys17作为Fmoc-Lys(Dde)-OH并入用于正交偶联。前9个氨基酸和第24号氨基酸(从C末端计数)是双重偶联的,意味着在去保护之前所述结构单元被偶联两次。在N末端并入Boc-Tyr(tBu)-OH作为最终的结构单元。
去保护
将哌啶/DMF(20%;10ml)添加到树脂中用于初始去保护,并且通过微波加热(30秒;40℃)混合物。将反应容器排干,添加第二部分的哌啶/DMF(20%;10ml)并且再次加热(75℃;3分钟)。然后用DMF洗涤(6×10ml)树脂。
侧链酰化
当肽仍与树脂相连时,使用在NMP中新制备的水合肼(2-4%)选择性地切割正交侧链保护基团2×15分钟。首先使用如上所述的标准偶联和去保护条件,将未保护的赖氨酸侧链与Fmoc-Glu-OtBu和两个Peg3结构单元偶联。最后,使用标准偶联条件,再次将亲脂性部分作为19-羧基-十九烷酸单叔丁基酯并入。
切割
将树脂用EtOH(3×10ml)和Et2O(3×10ml)洗涤,并在室温(r.t.)下干燥至恒重。通过用TFA/TIS/H2O(95/2.5/2.5;60ml,2h;r.t.)处理将粗制肽从树脂上切割下来。在减压下除去大部分TFA,使粗制肽沉淀并用***洗涤三次,在室温下干燥至恒重。
粗制肽的HPLC纯化
使用配备有Gemini NX 5μC-18110A,10×250mm柱和Gilson GX281级分收集器的Gilson 331泵,用缓冲液A(0.1%TFA,水溶液)和缓冲液B(0.1%TFA,90%MeCN,水溶液)的梯度以47ml/分钟运行,通过制备型反相HPLC将粗制肽首先由30%进行纯化。通过分析型HPLC和MS对级分进行分析,并将相关级分合并并冻干。使用相同的方法进行第二次纯化以获得纯度为96%的产物(53mg),如通过HPLC和MS所表征的。单一同位素质量计算值=5025,54,实测值为5025,72。
实施例2
人GIP受体(GIP R)活性测定
如本发明概述的,通过使用来自Perkin-Elmer的cAMP试剂盒并根据说明书,在用GIP或其类似物刺激各自受体之后,通过测量cAMP的诱导来评估本发明的肽缀合物的体外作用。简言之,将表达人GIP R的HEK293细胞(通过用人GIP R的cDNA转染并且选择稳定克隆产生的稳定细胞系)以30,000个细胞/孔接种在包被有0.01%聚L-赖氨酸的96孔微量滴定板上,在200μl生长培养基(DMEM,10%FCS,青霉素(100IU/ml)、链霉素(100μg/ml))中生长一天。在分析当天,移除生长培养基并将细胞用150μl台氏缓冲液(Tyrode’sSalts(9.6g/l),10mM HEPES,pH 7.4)洗涤一次。然后将细胞在含有升高浓度的对照化合物和测试化合物的100μl测定缓冲液(台氏缓冲液中0.1%W/V碱处理的酪蛋白和100μM IBMX)中于37℃下孵育15分钟。移除测定缓冲液并将细胞在每孔80μl裂解缓冲液(0.1%w/v BSA,5mM HEPES,0.3%v/v Tween-20)中裂解。从每个孔转移10μl裂解的细胞到384孔板中,并且与15μl珠-混合物(测定缓冲液中1单位/15μl抗cAMP接受体(Acceptor)珠,1单位/15μl供体珠和1单位/15μl生物素化的cAMP)混合。将板混合并且在室温下黑暗孵育1小时,之后使用EnvisionTM平板阅读器(Perkin-Elmer)测量。
使用在含有0.1%(v/v)DMSO的KRBH缓冲液中制备的cAMP标准曲线将结果转化成cAMP浓度。将所得cAMP曲线绘制成相对于log(测试化合物浓度)的绝对cAMP浓度(nM),并使用曲线拟合程序XLfit进行分析。
描述每种测试化合物对受体的效力和激动剂活性二者的所计算参数为:
EC 50,导致cAMP水平半数最大提高的浓度,反映了测试化合物的效力。结果总结在表2中。
表2:与对照肽相比,化合物对GIP-R的EC50平均值。
实施例3
人GIP受体(GIP R)和人GLP-1受体(GLP-1R)的活性测定
使用来自Perkin-Elmer的cAMP试剂盒并根据说明书,在用各自受体刺激之后,通过测量cAMP的诱导来评估肽缀合物的体外作用。简言之,将表达GIP R或GLP-1R的HEK293细胞(通过含有所讨论受体的cDNA的表达载体的转染并且选择稳定克隆产生的稳定细胞系)以30,000个细胞/孔接种在包被有0.01%聚L-赖氨酸的96孔微量滴定板上,在200μl生长培养基(DMEM,10%FCS,青霉素(100IU/ml)、链霉素(100μg/ml))中培养生长一天。在分析当天,移除生长培养基并将细胞用150μl台氏缓冲液(Tyrode’s Salts(9.6g/l),10mM HEPES,pH 7.4)洗涤一次。然后将细胞在含有升高浓度的对照化合物和测试化合物的100μl测定缓冲液(台氏缓冲液中0.05%W/V碱处理的酪蛋白和100μM IBMX)中于37℃下孵育15分钟。移除测定缓冲液并将细胞在每孔80μl裂解缓冲液(0.1%w/v BSA,5mM HEPES,0.3%v/v Tween-20)中裂解。从每个孔转移10μl裂解的细胞到384孔平板中,并且与15μl珠混合物(测定缓冲液中1单位/15μl抗cAMP接受者珠,1单位/15μl供体珠和1单位/15μl生物素化的cAMP)混合。将平板混合并且在室温下黑暗孵育1小时,之后使用EnvisionTM平板读板仪(Perkin-Elmer)测量。
相对于阳性和阴性对照(分别为参照激动剂(0.1nM人GIP或1nM Exendin-4)和测定缓冲液),将cAMP应答归一化以由使用4参数对数(4PL)非线性回归模型进行了曲线拟合的浓度响应曲线计算EC50和最大响应。
EC50(导致cAMP水平半数最大提高的浓度)总结在表2a中,反映了测试激动剂化合物的效力。
表2a:与对照肽相比,化合物的EC50平均值。NT=未测试,NA=无活性。
实施例4
选定化合物在小鼠中的药代动力学
方法
向C57BL/6J小鼠(体重为约25g的雄性)单次皮下(s.c.)推注或单次静脉内(i.v.)推注给予待测试的每种肽。
在皮下施用选定化合物(50、100或200nmol/kg)之后,在给药后直到96小时的8(八)个时间点抽取血样。在静脉内施用选定化合物(50、100或200nmol/kg)后,在给药后直到72小时的8(八)个时间点抽取血样。通过舌下采血抽取血样。给药载剂是含甘露醇的磷酸盐缓冲液(pH 7.5)。
在每个取样时间点,从两只小鼠抽取样品,即,对于每种化合物和每种施用途径包括了16只小鼠。在取血样之后,通过颈椎脱臼法立即处死小鼠。在固相萃取(SPE)或蛋白质沉淀后,通过液相色谱质谱(LC-MS/MS),对血浆样品进行分析。利用Phoenix WinNonlin6.3中的非分区法,使用平均血浆浓度来计算药代动力学参数。血浆终末清除半衰期(T1/2)测定为ln(2)/λz,其中λz是终末阶段期间log浓度对时间曲线的log线性回归的斜率大小。生物利用度被确定为AUCinf(s.c)/AUCinf(i.v)×100,其中AUCinf是外推到无穷大的血浆浓度-时间曲线下面积(AUCinf=AUC最终+C最终/λz,其中C最终是最终观察到的血浆浓度)。Tmmax是观察到最大血浆浓度时的给药后时间。结果总结在表3中。
表3.在皮下和静脉内施用选定化合物后,小鼠中的终末清除半衰期(h)和生物利用度。
*:生物利用度上限为100%
Λ:在重复测试中,化合物10的生物利用度为77%,化合物12的生物利用度为98%。
实施例5
在正常小鼠中的OGTT(口服葡萄糖耐量测试)。
使用标准饲料(Altromin 1324,Brogaarden A/S,Gentofte,Denmark)和添加柠檬酸至pH约3.6的家庭用水喂养雄性C57BL/6J小鼠(Charles River,Germany)。将动物以每组3只圈养在光照、温度和湿度控制的房间(12:12小时光暗循环中,光照为06.00-18.00时;21±1℃;50-80%相对湿度)。在OGTT前,将10至12周龄的小鼠禁食5小时。在经口强饲葡萄糖(t=0分钟;2g/kg;5mL/kg)前4小时,经皮下(s.c.)施用(5mL/kg)GIP受体激动剂(3-300nmol/kg)、GLP-1类似物利拉鲁肽(10nmol/kg)和载剂。在时间t=0(葡萄糖施用前)、15、30、60和120分钟取尾静脉血用于血糖测量。来自2次实验的结果(血糖水平和血糖曲线下面积(AUC),数据为平均值±SEM;n=6)示于图1(A-D)和图2(A-E)中。
使用Graph Pad Prism第5版进行统计学分析。使用单因素方差分析(one-wayANOVA)比较血糖AUC,之后通过Dunnett多重比较测试与载剂组。p<0.05时,认为差异是统计学显著的。相对于载剂的统计学显著性:*p<0.05,**p<0.01,***p<0.001。
实施例6
GIP受体激动剂和GLP-1受体激动剂的共同处理对饮食诱导的肥胖(DIO)C57BL/6J
小鼠体重的亚长期作用
使用经高脂饲料(总能量的45%来自脂肪,D12451,Research Diet Inc.)喂养约4个月的雄性C57BL/6J(JAX)小鼠(Charles River,UK)。将动物以每组3只圈养在光照、温度和湿度控制的房间(12:12小时的光暗循环,光照为07.00-19.00时;21±2℃;55±20%的相对湿度)。在开始模拟阶段之前,将小鼠单独圈养两周。对所有小鼠模拟处理(每天一次皮下注射载剂)一周以使动物适应操作和注射。随后,将小鼠按体重分级成处理组(n=8至9)。平均起始体重是39至40克。此后,从第1天至第22天每天用两次单独的皮下注射(每次注射3mL/kg)处理动物一次。第一次注射为用载剂1(25mM磷酸盐,125mM氯化钠缓冲液,pH 7.4)或GLP-1类似物利拉鲁肽(20nmol/kg)。第二次注射为用载剂2(25mM磷酸盐,205mM D-甘露醇,pH 7.5)或GIP激动剂(3和30nmol/kg)。GIP激动剂仅在研究的每个第三天给药(从第1天开始)。在其他天,用载剂2替换GIP激动剂。每日的注射在早上进行(在9.00-10.00)。整个研究中每天测定体重。在研究期间的体重变化如图3所示(Δ=每个研究日的体重-第1天的体重。数据是平均值±SEM)。
使用Graph Pad Prism第5版进行统计学分析。通过双因素方差分析随后用Bonferroni事后检验比较利拉鲁肽处理的小鼠与共施用利拉鲁肽和GIP激动剂的小鼠的体重变化。P<0.05认为是统计学显著的。通过双因素方差分析随后用Bonferroni事后检验比较载剂处理的对照小鼠与化合物处理的小鼠的体重变化。***相对于载剂p<0.001。图3中示出了第22天相对于载剂的统计学差异。
实施例7
GIP受体激动剂和GLP-1受体激动剂的共处理对饮食诱导的肥胖(DIO)C57BL/6J小
鼠中体重的些长期作用
使用经高脂饲料(总能量的60%来自脂肪,来自TestDiet的DIO Rodent Purified58Y1-58126)喂养约5个月的雄性C57BL/6J小鼠(Charles River,Germany)。将动物以每组n=3只圈养在光照、温度和湿度控制的房间(12:12小时的光暗循环,光照为06.00-18.00时;21±1℃;65±15%相对湿度)。对所有小鼠模拟处理(每天一次皮下注射载剂)一周以使动物适应操作和注射。随后,将小鼠按体重分级成处理组(n=9)。平均起始体重是40至41克。此后,从第0天至第27天每天用两次单独的皮下注射(每次注射5mL/kg)处理动物一次。第一次注射为用载剂1(25mM磷酸盐,125mM氯化钠缓冲液,pH 7.4)或GLP-1类似物利拉鲁肽(20nmol/kg)。第二次注射为用载剂2(25mM磷酸盐,205mM D-甘露醇,pH 7.5)或GIP激动剂(30和/或300nmol/kg)。GIP激动剂仅在研究的每个第三天给药(从第0天开始)。在其他天,用载剂2替换GIP激动剂。每日注射在早上进行(在9.00-10.00)。整个研究中每天测定体重。在研究期间的体重变化如图4A(化合物10和12)、B(化合物17)、C(化合物18)、D(化合物35)和E(化合物41)所示(Δ体重=每个研究日的体重-第0天的体重。数据是平均值±SEM)。
使用Graph Pad Prism第5版进行统计学分析。通过双因素方差分析随后用Bonferroni事后检验比较利拉鲁肽处理的小鼠与共施用利拉鲁肽和GIP激动剂的小鼠的体重变化。P<0.05认为是统计学显著的(在体重曲线下用线示出)。通过双因素方差分析随后用Bonferroni事后检验比较载剂处理的对照小鼠与化合物处理的小鼠的体重变化。***相对于载剂p<0.001。示出了第27天相对于载剂的统计学差异(图4A-E)。
Claims (16)
1.下式的GIP类似物:
H-Y-Aib-EGTFISDYSIELDK-K((19-羧基-十九烷酰基)-[(哌嗪-1-基)-乙酰基]-Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2
或其可药用盐或溶剂合物。
2.药物组合物,其包含与载体混合的根据权利要求1所述的GIP类似物,或其可药用盐或溶剂合物。
3.根据权利要求2所述的药物组合物,其被配制成适于通过注射或输注施用的液体。
4.根据权利要求2所述的药物组合物,其被配制成使得所述GIP类似物受控释放。
5.根据权利要求4所述的药物组合物,其被配制成使得所述GIP类似物缓慢释放。
6.根据权利要求1所述的GIP类似物或其可药用盐或溶剂合物在制备用于治疗和/或预防糖尿病或糖尿病相关紊乱,或肥胖或肥胖相关紊乱的药物中的用途。
7.根据权利要求6所述的用途,其中所述糖尿病相关紊乱是胰岛素抵抗、葡萄糖耐受不良、空腹血糖升高、低血糖症、前驱糖尿病、1型糖尿病、2型糖尿病、妊娠期糖尿病高血压、血脂异常或其组合。
8.根据权利要求7所述的用途,其中所述低血糖症是胰岛素治疗诱导的低血糖症。
9.根据权利要求6所述的用途,其中所述糖尿病相关紊乱是动脉硬化、冠心病、外周动脉疾病、中风;或者是与以下相关的病症:致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态或促炎状态。
10.根据权利要求6所述的用途,其中所述糖尿病相关紊乱是动脉粥样硬化。
11.根据权利要求6所述的用途,其中所述糖尿病相关紊乱是骨质疏松症。
12.根据权利要求6所述的用途,其中所述糖尿病相关紊乱是骨折风险升高。
13.根据权利要求9所述的用途,其中所述血脂紊乱是高甘油三酯、低HDL胆固醇、高LDL胆固醇、动脉壁中斑块堆积或其组合。
14.根据权利要求9所述的用途,其中所述血栓前状态包括血液中高纤维蛋白原水平或血液中高纤溶酶原激活物抑制剂-1水平。
15.根据权利要求9所述的用途,其中所述促炎状态包括血液中C反应蛋白水平升高。
16.根据权利要求6所述的用途,其中所述肥胖相关紊乱是肥胖关联的炎症、肥胖关联的胆囊疾病或肥胖诱发的睡眠呼吸暂停,或者与选自以下的病症相关:致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态和促炎状态或其组合。
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WO2020067575A1 (en) | 2018-09-24 | 2020-04-02 | Takeda Pharmaceutical Company Limited | Gip receptor agonist peptide compounds and uses thereof |
TWI764209B (zh) * | 2019-08-01 | 2022-05-11 | 美商美國禮來大藥廠 | Gipr促效劑化合物 |
TW202120535A (zh) * | 2019-11-15 | 2021-06-01 | 大陸商江蘇豪森藥業集團有限公司 | 受體雙重激動劑化合物及其醫藥組成物 |
MX2022011089A (es) | 2020-03-06 | 2022-10-03 | Sanofi Sa | Peptidos como agonistas selectivos del receptor de gip. |
WO2021198229A1 (en) | 2020-03-31 | 2021-10-07 | Antaros Medical Ab | Selective gip receptor agonists comprising a chelating moiety for imaging and therapy purposes |
KR20230125093A (ko) | 2021-01-20 | 2023-08-28 | 바이킹 테라퓨틱스 인코포레이티드 | 대사 및 간 질환 치료를 위한 조성물 및 방법 |
CN118159552A (zh) | 2021-09-06 | 2024-06-07 | 赛诺菲 | 作为强效的且选择性的gip受体激动剂的新肽 |
WO2023084118A1 (en) | 2021-11-15 | 2023-05-19 | Adocia | Solid compositions comprising a peptide or a protein and an acylated amino acid |
EP4299057A1 (en) | 2022-06-30 | 2024-01-03 | Adocia | Solid compositions comprising a peptide or a protein and an acylated amino acid |
EP4180060A1 (en) | 2021-11-15 | 2023-05-17 | Adocia | Solid compositions comprising a peptide or a protein and an acylated amino acid |
EP4299052A1 (en) | 2022-06-30 | 2024-01-03 | Adocia | Solid compositions comprising a peptide or a protein and a permeation enhancer |
EP4299071A1 (en) | 2022-07-01 | 2024-01-03 | Adocia | Compositions comprising a peptide or a protein and an acylated amino acid |
WO2024068848A1 (en) | 2022-09-28 | 2024-04-04 | Zealand Pharma A/S | Methods for treating obesity |
CN118255864A (zh) * | 2022-12-26 | 2024-06-28 | 杭州中美华东制药有限公司 | Gip受体激动剂及其用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013164483A1 (en) * | 2012-05-03 | 2013-11-07 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
CN103764673A (zh) * | 2011-06-10 | 2014-04-30 | 北京韩美药品有限公司 | 葡萄糖依赖性促胰岛素多肽类似物、其药物组合物及应用 |
Family Cites Families (173)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4288627A (en) | 1980-02-12 | 1981-09-08 | Phillips Petroleum Company | Oxidation of thiols employing cobalt molybdate/triethylamine catalyst |
NZ202757A (en) | 1981-12-23 | 1985-11-08 | Novo Industri As | Peptides and medicaments |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
ES2113879T3 (es) | 1990-01-24 | 1998-05-16 | Douglas I Buckley | Analogos de glp-1 utiles para el tratamiento de diabetes. |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
CA2082279C (en) | 1990-05-09 | 2007-09-04 | Grethe Rasmussen | Cellulase preparation comprising an endoglucanase enzyme |
DK36392D0 (da) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | Anvendelse af kemisk forbindelse |
US5846747A (en) | 1992-03-25 | 1998-12-08 | Novo Nordisk A/S | Method for detecting glucagon-like peptide-1 antagonists and agonists |
DK39892D0 (da) | 1992-03-25 | 1992-03-25 | Bernard Thorens | Peptid |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
AU7531094A (en) | 1993-08-24 | 1995-03-21 | Novo Nordisk A/S | Protracted glp-1 |
ES2154299T3 (es) | 1993-09-07 | 2001-04-01 | Amylin Pharmaceuticals Inc | Metodos para la regulacion de la motilidad gastrointestinal. |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5523449A (en) | 1995-05-17 | 1996-06-04 | Bayer Corporation | Process for preparing phosphorodichlorido-dithioates by reacting alkylmercaptans with phosphorus trichloride in the presence of sulfur |
CN1183158C (zh) | 1996-06-05 | 2005-01-05 | 罗赫诊断器材股份有限公司 | Exendin类似物,其制备方法及含有它们的药物制剂 |
US6110703A (en) | 1996-07-05 | 2000-08-29 | Novo Nordisk A/S | Method for the production of polypeptides |
PT966297E (pt) | 1996-08-08 | 2009-03-18 | Amylin Pharmaceuticals Inc | Regulação da motilidade gastrintestinal |
US6956026B2 (en) | 1997-01-07 | 2005-10-18 | Amylin Pharmaceuticals, Inc. | Use of exendins for the reduction of food intake |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
JP3149958B2 (ja) | 1996-08-30 | 2001-03-26 | ノボ ノルディスク アクティーゼルスカブ | Glp―1誘導体 |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
CA2265454A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Peptide prodrugs containing an alpha-hydroxyacid linker |
AU723268B2 (en) | 1996-09-09 | 2000-08-24 | Zealand Pharma A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
WO1998022577A1 (en) | 1996-11-15 | 1998-05-28 | Maria Grazia Masucci | Fusion proteins having increased half-lives |
US6136784A (en) | 1997-01-08 | 2000-10-24 | Amylin Pharmaceuticals, Inc. | Amylin agonist pharmaceutical compositions containing insulin |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
CA2279836A1 (en) | 1997-02-05 | 1998-08-13 | 1149336 Ontario Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
US5846937A (en) | 1997-03-03 | 1998-12-08 | 1149336 Ontario Inc. | Method of using exendin and GLP-1 to affect the central nervous system |
CA2289094A1 (en) | 1997-05-07 | 1998-11-12 | Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V., Berlin | New cysteine derivatives, processes for their production, and pharmaceuticals containing them |
US7157555B1 (en) | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
JP2001513512A (ja) | 1997-08-08 | 2001-09-04 | アミリン・ファーマシューティカルズ,インコーポレイテッド | 新規なエキセンディン作動剤化合物 |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
BR9814189A (pt) | 1997-11-14 | 2000-10-03 | Amylin Pharmaceuticals Inc | "compostos agonistas da exendina" |
US7220721B1 (en) | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
ES2294822T3 (es) | 1997-11-14 | 2008-04-01 | Amylin Pharmaceuticals, Inc. | Compuestos novedosos de agonistas de exendina. |
EP1049486A4 (en) | 1997-12-05 | 2006-01-04 | Lilly Co Eli | GLP-1 FORMULATIONS |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
CA2320371C (en) | 1998-02-13 | 2012-01-17 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and glp-1 |
JP2002506792A (ja) | 1998-02-27 | 2002-03-05 | ノボ ノルディスク アクティーゼルスカブ | N末端修飾glp−1誘導体 |
WO1999043708A1 (en) | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
IL138214A0 (en) | 1998-03-09 | 2001-10-31 | Zealand Pharmaceuticals As | Pharmacolgically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
ATE269103T1 (de) | 1998-03-13 | 2004-07-15 | Novo Nordisk As | Stabilisierte wässerige glukagonlösungen enthaltend detergenzien |
WO1999049788A1 (en) | 1998-03-30 | 1999-10-07 | Focus Surgery, Inc. | Ablation system |
SE9802080D0 (sv) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome and new use of substances therein |
DE69941510D1 (de) | 1998-08-10 | 2009-11-19 | Us Gov Nat Inst Health | Differenzierung von nicht-insulin in insulin-produzierende zellen durch glp-1 und exendin-4 und dessen verwendung |
WO2000020592A1 (en) | 1998-10-07 | 2000-04-13 | Medical College Of Georgia Research Institute, Inc. | Glucose-dependent insulinotropic peptide for use as an osteotropic hormone |
US6284725B1 (en) | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
CZ295890B6 (cs) | 1998-12-07 | 2005-11-16 | Societe De Conseils De Recherches Et D'application | Analogy GLP-1, mající kyselinu aminoizomáselnou pozici 8 a D-arginin na pozici 36, jejich použití a farmaceutické prostředky je obsahující |
US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
NZ512657A (en) | 1999-01-14 | 2004-01-30 | Amylin Pharmaceuticals Inc | Glucagon suppression |
DE60021166T3 (de) | 1999-01-14 | 2019-08-22 | Amylin Pharmaceuticals, Llc | Neue exendin agonist formulierungen und deren verabreichung |
US6451987B1 (en) | 1999-03-15 | 2002-09-17 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides |
US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
ATE409193T1 (de) | 1999-03-17 | 2008-10-15 | Novo Nordisk As | Verfahren zur acylierung von peptiden und proteinen |
WO2000058360A2 (en) | 1999-03-29 | 2000-10-05 | Uutech Limited | Analogs of gastric inhibitory peptide and their use for treatment of diabetes |
GB0404124D0 (en) | 2004-02-25 | 2004-03-31 | Univ Ulster | Antagonists of GIP |
US6271241B1 (en) | 1999-04-02 | 2001-08-07 | Neurogen Corporation | Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors |
US6924264B1 (en) | 1999-04-30 | 2005-08-02 | Amylin Pharmaceuticals, Inc. | Modified exendins and exendin agonists |
BR0010705A (pt) | 1999-04-30 | 2002-02-05 | Amylin Pharmaceuticals Inc | Exendinas modificadas e agonistas da exendina |
PT1180121E (pt) | 1999-05-17 | 2004-03-31 | Conjuchem Inc | Peptidos insulinotropicos de longa duracao |
US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
US6506724B1 (en) | 1999-06-01 | 2003-01-14 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus |
US6344180B1 (en) | 1999-06-15 | 2002-02-05 | Bionebraska, Inc. | GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type II diabetes |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
US6586438B2 (en) | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
AU775663B2 (en) | 2000-10-20 | 2004-08-12 | Amylin Pharmaceuticals, Inc. | Treatment of hibernating myocardium and diabetic cardiomyopathy with a GLP-1 peptide |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
WO2003053460A1 (en) | 2001-12-19 | 2003-07-03 | Eli Lilly And Company | Crystalline compositions for controlling blood glucose |
SK2432004A3 (sk) | 2001-12-20 | 2005-04-01 | Eli Lilly And Company | Inzulínová zlúčenina s protrahovaným účinkom |
US20030232761A1 (en) * | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
EP1837031B1 (en) | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
ES2327328T3 (es) | 2002-07-04 | 2009-10-28 | Zealand Pharma A/S | Glp-1 y procedimientos para el tratamiento de la diabetes. |
RU2376314C2 (ru) | 2002-10-02 | 2009-12-20 | Зилэнд Фарма А/С | Стабилизированные соединения эксендина-4 |
US7192922B2 (en) | 2002-11-19 | 2007-03-20 | Allegheny-Singer Research Institute | Method of treating left ventricular dysfunction |
GB0300571D0 (en) | 2003-01-10 | 2003-02-12 | Imp College Innovations Ltd | Modification of feeding behaviour |
KR20050121748A (ko) | 2003-04-29 | 2005-12-27 | 일라이 릴리 앤드 캄파니 | 연장된 시간 작용을 갖는 인슐린 유사체 |
CA2523408A1 (en) | 2003-05-09 | 2004-11-18 | Novo Nordisk A\S | Peptides for use in treating obesity |
US7623530B2 (en) | 2003-11-20 | 2009-11-24 | Nokia Corporation | Indication of service flow termination by network control to policy decision function |
RU2006131046A (ru) | 2004-01-30 | 2008-03-10 | Уэрейта Фармасьютикалз, Инк. (Ca) | Совместное применение агониста glp-1 и соединений гастрина |
CA2849552A1 (en) | 2004-02-11 | 2005-08-25 | Amylin Pharmaceuticals, Llc | Hybrid polypeptides with selectable properties |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
RU2413530C9 (ru) | 2004-11-12 | 2021-05-18 | Ново Нордиск А/С | Стабильные препараты инсулинотропных пептидов |
US8404637B2 (en) * | 2005-02-11 | 2013-03-26 | Amylin Pharmaceuticals, Llc | GIP analog and hybrid polypeptides with selectable properties |
TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
JP2008539735A (ja) | 2005-05-06 | 2008-11-20 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | グルカゴン様ペプチド1(glp−1)受容体アンタゴニストおよびそれらの薬理学的使用方法 |
EP2351776A1 (en) | 2005-06-13 | 2011-08-03 | Imperial Innovations Limited | Oxyntomodulin analogues and their effects on feeding behaviour |
DE102005034394A1 (de) | 2005-07-22 | 2007-02-01 | Airbus Deutschland Gmbh | Fixierfaden zum Heften von Verstärkungsfasern |
US20090202497A1 (en) | 2005-08-23 | 2009-08-13 | The General Hospital Corporation | Use of glp-1, glp-1 derivatives or glp-1 fragments for skin regeneration, stimulation of hair growth, or treatment of diabetes |
ES2572952T3 (es) | 2005-11-07 | 2016-06-03 | Indiana University Research And Technology Corporation | Análogos de glucagón que muestran solubilidad y estabilidad fisiológicas |
US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
WO2007095737A1 (en) | 2006-02-21 | 2007-08-30 | Waratah Pharmaceuticals Inc. | Combination therapy for the treatment of diabetes comprising an exendin agonist and a gastrin compound |
US7928058B2 (en) | 2006-02-22 | 2011-04-19 | Merck Sharp & Dohme Corp. | Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition |
ZA200900545B (en) | 2006-07-18 | 2010-03-31 | Sanofi Aventis | Antagonist antibody against EPHA2 for the treatment of cancer |
ITMI20061607A1 (it) | 2006-08-09 | 2008-02-10 | Maria Vincenza Carriero | Peptidi con attivita farmacologica |
ES2554773T3 (es) | 2006-10-04 | 2015-12-23 | Case Western Reserve University | Insulina y análogos de la insulina resistentes a la fibrilación |
CA2669806C (en) | 2006-11-08 | 2018-10-02 | Zealand Pharma A/S | Selective glucagon-like-peptide-2 (glp-2) analogues |
WO2008071010A1 (en) | 2006-12-12 | 2008-06-19 | Waratah Pharmaceuticals Inc. | Combination treatments with selected growth/hormone regulatory factors for diabetes and related diseases |
TWI428346B (zh) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | 新穎化合物及其等對進食行為影響 |
AU2008205229B2 (en) | 2007-01-05 | 2014-03-27 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility in physiological pH buffers |
WO2008101017A2 (en) | 2007-02-15 | 2008-08-21 | Indiana Unversity Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
FR2917552B1 (fr) | 2007-06-15 | 2009-08-28 | Sagem Defense Securite | Procede de regulation de la gigue de transmission au sein d'un terminal de reception |
ATE520714T1 (de) | 2007-06-15 | 2011-09-15 | Zealand Pharma As | Glucagonanaloga |
EP2025684A1 (en) | 2007-08-15 | 2009-02-18 | Zealand Pharma A/S | Glucagon analogues |
WO2009030738A1 (en) | 2007-09-05 | 2009-03-12 | Novo Nordisk A/S | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
NZ603812A (en) | 2007-11-20 | 2014-06-27 | Ambrx Inc | Modified insulin polypeptides and their uses |
GB2455553B (en) | 2007-12-14 | 2012-10-24 | Nuaire Ltd | Motor mounting assembly for an axial fan |
KR20100111683A (ko) | 2008-01-09 | 2010-10-15 | 사노피-아벤티스 도이칠란트 게엠베하 | 극히 지연된 시간-작용 프로필을 갖는 신규 인슐린 유도체 |
DE102008003566A1 (de) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
DE102008003568A1 (de) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
NZ586590A (en) | 2008-01-09 | 2012-06-29 | Sanofi Aventis Deutschland | Insulin analogues or derivatives having an extremely delayed time-action profile |
WO2009129250A2 (en) | 2008-04-14 | 2009-10-22 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
EP2296692A4 (en) | 2008-04-22 | 2012-06-06 | Univ Case Western Reserve | INSULIN ANALOGUES SPECIFIC TO ISOFORMS |
TWI451876B (zh) | 2008-06-13 | 2014-09-11 | Lilly Co Eli | 聚乙二醇化之離脯胰島素化合物 |
JP5753779B2 (ja) | 2008-06-17 | 2015-07-22 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションIndiana University Research And Technology Corporation | 生理学的pHの緩衝液中で向上した溶解性及び安定性を示すグルカゴン類縁体 |
WO2010011439A2 (en) | 2008-06-17 | 2010-01-28 | Indiana University Research And Technology Corporation | Gip-based mixed agonists for treatment of metabolic disorders and obesity |
EP2676673B1 (en) | 2008-06-17 | 2016-11-16 | Indiana University Research and Technology Corporation | Glucagon/glp-1 receptor co-agonists |
PL219335B1 (pl) | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | Pochodna insuliny lub jej farmaceutycznie dopuszczalna sól, jej zastosowanie oraz zawierająca ją kompozycja farmaceutyczna |
CN102171245B (zh) | 2008-07-31 | 2015-03-25 | 卡斯西部储备大学 | 卤素稳定型胰岛素 |
US9074014B2 (en) | 2008-08-07 | 2015-07-07 | Ipsen Pharma S.A.S. | Analogues of glucose-dependent insulinotropic polypeptide |
EP2340049B1 (en) | 2008-09-12 | 2015-11-11 | Novo Nordisk A/S | Method of acylating a peptide or protein |
BRPI0823377A2 (pt) | 2008-12-15 | 2016-09-27 | Zealand Pharma As | análogos de glucagon |
ES2439499T3 (es) | 2008-12-15 | 2014-01-23 | Zealand Pharma A/S | Análogos de glucagón |
BRPI0823378A2 (pt) | 2008-12-15 | 2019-09-24 | Zealand Pharma As | análogos de glucagon |
BRPI0823376A2 (pt) | 2008-12-15 | 2015-06-16 | Zealand Pharma As | Análagos de glucagon |
AU2009335715B2 (en) | 2008-12-19 | 2016-09-15 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
EP2376520B1 (en) | 2008-12-19 | 2014-02-12 | Indiana University Research&Technology Corporation | Insulin analogs |
WO2010096052A1 (en) | 2009-02-19 | 2010-08-26 | Merck Sharp & Dohme Corp. | Oxyntomodulin analogs |
WO2010107487A2 (en) | 2009-03-18 | 2010-09-23 | Wu Nian | Lipid-drug conjugates for drug delivery |
CN101519446A (zh) | 2009-03-31 | 2009-09-02 | 上海一就生物医药有限公司 | 一种重组人胰岛素及其类似物的制备方法 |
PE20120914A1 (es) | 2009-06-16 | 2012-08-22 | Univ Indiana Res & Tech Corp | Compuestos glucagon activo de receptor de gip |
KR101809024B1 (ko) | 2009-07-13 | 2017-12-14 | 질랜드 파마 에이/에스 | 아실화 글루카곤 유사체 |
MX2012006634A (es) | 2009-12-16 | 2012-06-21 | Novo Nordisk As | Derivados de peptidos tipo glucagon 1 de doble acilato. |
WO2011084808A2 (en) | 2009-12-21 | 2011-07-14 | Amunix Operating Inc. | Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases |
EA026384B1 (ru) | 2010-01-20 | 2017-04-28 | Зилэнд Фарма А/С | Лечение заболеваний сердца |
IN2012DN06437A (zh) * | 2010-01-27 | 2015-10-09 | Univ Indiana Res & Tech Corp | |
US20130143798A1 (en) | 2010-03-26 | 2013-06-06 | Novo Nordisk A/S | Novel glucagon analogues |
WO2011117417A1 (en) | 2010-03-26 | 2011-09-29 | Novo Nordisk A/S | Novel glucagon analogues |
AR080592A1 (es) | 2010-03-26 | 2012-04-18 | Lilly Co Eli | Peptido con actividad para el gip-r y glp-1-r, formulacion famaceutica que lo comprende, su uso para preparar un medicamento util para el tratamiento de diabetes mellitus y para inducir la perdida de peso |
CN103003300B (zh) | 2010-04-27 | 2017-06-09 | 西兰制药公司 | Glp‑1受体激动剂和胃泌素的肽缀合物及其用途 |
CA2797431C (en) | 2010-04-27 | 2016-06-21 | Zhejiang Beta Pharma Inc. | Glucagon-like peptide-1 analogue and use thereof |
AR081975A1 (es) | 2010-06-23 | 2012-10-31 | Zealand Pharma As | Analogos de glucagon |
MX2012014961A (es) | 2010-06-24 | 2013-02-26 | Zealand Pharma As | Analogos de glucagon. |
US9708383B2 (en) | 2010-11-09 | 2017-07-18 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
EA201390796A1 (ru) | 2011-01-20 | 2014-07-30 | Зилэнд Фарма А/С | Применение ацилированного аналога глюкагона |
AU2012234276A1 (en) | 2011-03-28 | 2013-08-29 | Novo Nordisk A/S | Novel glucagon analogues |
EP2694095B1 (en) | 2011-04-05 | 2018-03-07 | Longevity Biotech, Inc. | Compositions comprising glucagon analogs and methods of making and using the same |
AU2012241894B2 (en) | 2011-04-12 | 2015-12-03 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
WO2012150503A2 (en) | 2011-05-03 | 2012-11-08 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
EP2707713A2 (en) | 2011-05-10 | 2014-03-19 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
BR112014006684A2 (pt) | 2011-09-23 | 2017-03-28 | Novo Nordisk As | análogos de glucagon |
US9259477B2 (en) | 2011-11-03 | 2016-02-16 | Zealand Pharma A/S | GLP-1 receptor agonist peptide gastrin conjugates |
JP2015502380A (ja) | 2011-12-23 | 2015-01-22 | ジーランド ファーマ アクティーゼルスカブ | グルカゴン類似体 |
EA028929B1 (ru) | 2012-05-03 | 2018-01-31 | Зилэнд Фарма А/С | Аналоги глюкагоноподобного пептида-2 (glp-2) |
EP2863954A1 (en) | 2012-06-21 | 2015-04-29 | Indiana University Research and Technology Corporation | Incretin receptor ligand polypeptide fc-region fusion polypeptides and conjugates with altered fc-effector function |
CN109456400A (zh) | 2012-07-23 | 2019-03-12 | 西兰制药公司 | 胰高血糖素类似物 |
TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
KR20150096684A (ko) | 2012-12-21 | 2015-08-25 | 사노피 | 엑센딘-4 유도체 |
PT3057984T (pt) | 2013-10-17 | 2018-10-24 | Boehringer Ingelheim Int | Análogos de glucagon acilados |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
EP3066117B1 (en) | 2013-11-06 | 2019-01-02 | Zealand Pharma A/S | Glucagon-glp-1-gip triple agonist compounds |
JP6682432B2 (ja) | 2013-11-06 | 2020-04-15 | ジーランド ファーマ アクティーゼルスカブ | Gip−glp−1デュアルアゴニスト化合物及び方法 |
WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
KR20160114082A (ko) | 2014-02-18 | 2016-10-04 | 노보 노르디스크 에이/에스 | 안정한 글루카곤 유사체 및 저혈당증의 치료를 위한 용도 |
EP3212218B1 (en) | 2014-10-29 | 2021-06-30 | Zealand Pharma A/S | Gip agonist compounds and methods |
CN107636010B (zh) | 2015-04-16 | 2021-10-01 | 西兰制药公司 | 酰化胰高血糖素类似物 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103764673A (zh) * | 2011-06-10 | 2014-04-30 | 北京韩美药品有限公司 | 葡萄糖依赖性促胰岛素多肽类似物、其药物组合物及应用 |
WO2013164483A1 (en) * | 2012-05-03 | 2013-11-07 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
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