TW201941771A - 糖尿病性腎病之預防藥及／或治療藥 - Google Patents
糖尿病性腎病之預防藥及／或治療藥 Download PDFInfo
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- TW201941771A TW201941771A TW107134300A TW107134300A TW201941771A TW 201941771 A TW201941771 A TW 201941771A TW 107134300 A TW107134300 A TW 107134300A TW 107134300 A TW107134300 A TW 107134300A TW 201941771 A TW201941771 A TW 201941771A
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- diabetic nephropathy
- parovatin
- diabetes
- renal
- rarγ agonist
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Abstract
本發明之課題為提供一種可預防或治療糖尿病性腎病之藥劑。
本發明之解決手段為含有RARγ促效劑作為有效成分之糖尿病性腎病之預防藥及/或治療藥。亦提供腎性貧血之預防藥及/或治療藥、腎小球環間膜細胞中IV型膠原蛋白的表現抑制藥劑、腎小球環間膜細胞中BMP4的表現抑制藥劑、腎小管基質中的纖維化抑製藥劑。
本發明之解決手段為含有RARγ促效劑作為有效成分之糖尿病性腎病之預防藥及/或治療藥。亦提供腎性貧血之預防藥及/或治療藥、腎小球環間膜細胞中IV型膠原蛋白的表現抑制藥劑、腎小球環間膜細胞中BMP4的表現抑制藥劑、腎小管基質中的纖維化抑製藥劑。
Description
本發明係關於糖尿病性腎病之預防藥及/或治療藥。
澱粉等糖質(碳水化物)是維持人類生命最重要的營養素之一，糖質被消化形成葡萄糖(glucose)，從血液中進入全身的細胞並作為主要能量源被利用。血液中的葡萄糖稱為血糖，若透過用餐等方式攝取碳水化物則血糖値會升高，另一方面，藉由運動等方式使葡萄糖作為能量被消費而使血糖値降低。健康人體的狀況下，會藉由胰島素及具有與胰島素相反功能的荷爾蒙之平衡，而將血糖值控制在固定範圍內，故即使用餐或運動也不會造成血糖値的極端變動。
糖尿病是指因胰島素無法充分作用故葡萄糖無法有效被利用，而使血糖値呈升高狀態，若放置不管則會造成各種影響。糖尿病依其原因分為1型糖尿病、2型糖尿病、特殊原因所造成其他糖尿病、妊娠糖尿病之4種類型。該等中，以患者數量觀點來看尤其以2型糖尿病最為重要。
2型糖尿病是因胰島素分泌少或功能差等原因所產生。主要見於中高年以後，但近年來在年輕層的發病亦在增加。以日本而言，糖尿病患者約90%為2型糖尿病。2型糖尿病會因遺傳性體質且過食(特別是高脂肪食)、運動不足、肥胖，壓力等生活習慣或年齡增加等因素而發病。又，即使不是肥胖，若成為內臓脂肪增加之稱為代謝症候群的狀態，也會變得容易發病。
2型糖尿病會在未注意情況下發病且進展緩慢，故糖尿病會在沒有症狀之狀態下進展。接著，因無症狀而未進行血糖控制，則會引起以下所示併發症。
併發症可大致分為微血管病變與大血管病變。微血管病變係以見於微血管之糖尿病特徵性併發症，像是糖尿病性視網膜病變、糖尿病性腎病、糖尿病性神經障害之3種類型(又稱為糖尿病之三大併發症)。大血管病變係大血管病變之動脈硬化所引起併發症，可分為中風、心肌梗塞、周邊動脈性疾病(腳的壞疽等)。
根據日本國厚生勞動省之平成28年「國民健康、營養調査」(http://www.seikatsusyukanbyo.com/statistics/2017/009436.php) (非專利文獻1)，「強烈懷疑有糖尿病者」之比例為12.1%，估計約1000萬人。又，「無法否定糖尿病可能性者」之比例亦為12.1%，估計約1000萬人。亦即，糖尿病患者及糖尿病危險群各估計約有1000萬人。
根據國際糖尿病聯盟(IDF)之發表(全球糖尿病概覽第7版：http://www.diabetesatlas.org/)(非專利文獻2)，世界糖尿病人口持續爆發性增加，在2015年的時間點糖尿病患者數達到4億1500萬人，較前年增加2830萬人。接著，若無有效對策，則到2040年預測會增加到6億4200萬人。2015年20~79歲成人之糖尿病患病率為8.8%，估計約每11人中就有1人為糖尿病患者。糖尿病關連醫療費約為6730億美元，佔世界主要國總醫療費的5~20%。糖尿病醫療費到2040年預測會增加至8020億美元。
如上述，糖尿病患者爆發性增加及其醫療費爆發性增加為世界性的一大問題，因而有各種糖尿病治療藥被開發。其中，糖尿病的主要治療為血糖控制及降壓療法。血糖控制以低卡路里餐、運動療法為基本，但亦進行服用糖尿病藥(DPP-4阻礙劑、GLP-1受體促效劑、SGLT2阻礙劑、SU劑、α葡萄糖苷酶阻礙劑、雙胍、速效型胰島素分泌促進劑、胰島素抵抗性改善劑、摻配劑等)、或注射胰島素。降壓療法有血管聚張素轉換酵素(ACE)阻礙藥、血管聚張素II受體拮抗劑(ARB)之投藥，視情形亦有鈣拮抗劑，利尿藥等其他種類降壓藥之投藥等。
另一方面，上述糖尿病之三大併發症中，糖尿病性腎病若症狀加重則血液中的代謝物會累積，進而引起腎衰竭或***等攸關生命之嚴重症狀。進一步，因患腎衰竭而需要進行人工透析。近年來，接受透析療法的新增病歷中，其原有疾病中有40%以上為糖尿病性腎病(http://www.jsdt.or.jp/overview_confirm.html)(非專利文獻3)，2008年以後幾乎是平坦地隨時間變化橫向推移(圖表 日本國慢性透析療法現況 2014年12月31日現今、日本透析醫學會發行2015年12月1日)。
以日本的情況而言，在2016年時間點，透析患者約為32萬人，以一年5000人數目持續增加。患者人數之增加速度與高齡化速度幾乎一致，預測此增加趨式會延續至2025年。對每一透析患者，國庫負擔一年約500萬日圓，單純計算下合計負擔1兆6000億日圓。又，透析患者多會產生併發症，若一併考慮併發症的費用則會有約2兆日圓醫療費(日本醫療費之5%)是用於透析患者，因此抑制透析患者人數是醫療經濟的緊急課題之一。針對此問題已提出以growth hormone(GH)/insulin-like growth factor(IGF1)系阻礙藥(Curr Diabetes Rev (2011) 7(1) 50(非專利文獻4))、Jak/Stat系阻礙藥(Diabetologia (2016) 59, 1624(非專利文獻5)；Diabetes (2009) 58, 469(非專利文獻6)；Nephrol Dial Transplant (2015) 30, iv54 (非專利文獻7))、CCL2=MCP1/CCR2拮抗劑(Biochem Biophys Res Commun (2007) 360, 772(非專利文獻8)；Diabetes Care (2009) 32 (3) 465(非專利文獻9))、Nrf2-Keap1系活化藥(N Engl J Med (2013) 369 (26) 2492(非專利文獻10)；Nephrol Dial Transplant (2013) 28, 2841(非專利文獻11)；N Engl J Med (2011) 365 (4) 327(非專利文獻12)；Am J Physiol Renal Physiol (2013) 304, F808(非專利文獻13))、Notch1系抑制藥(Nephrol Dial Transplant (2015) 30, iv54(非專利文獻7))、ETA
R拮抗劑(Nephrol Dial Transplant (2015) 30, iv54(非專利文獻7))等治療糖尿病性腎病之藥物，但其作用效果有限。
[先前技術文獻]
[非專利文獻]
[先前技術文獻]
[非專利文獻]
非專利文獻1：日本國厚生勞動省＜糖尿病患者及糖尿病危險群各估計約為1,000萬人＞ 2017 (http://www.seikatsusyukanbyo.com/statistics/2017/009436.php)。
非專利文獻2：國際糖尿病聯盟(International Diabetes Federation)＜全球糖尿病概覽第7版＞ 2015 (http://www.diabetesatlas.org/)。
非專利文獻3：日本透析醫學會＜圖表 日本國慢性透析療法現況 2014年12月31日現今、日本透析醫學會發行2015年12月1日＞ 2015(http://www.jsdt.or.jp/overview_confirm.html)。
非專利文獻4：Kumar PA, Brosius FC, Menon R. The Glomerular Podocyte as a Target of Growth Hormone Action: Implications for the Pathogenesis of Diabetic Nephropathy. Current Diabetes Reviews 2011; 7(1):50-55.
非專利文獻5：Brosius FC, Tuttle KR, Kretzler M. JAK inhibition in the treatment of diabetic kidney disease. Diabetologia 2016; 59(8):1624-1627.
非專利文獻6：Berthier CC, Zhang H, Schin ML, et al. Enhanced Expression of Janus Kinase-Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy. Diabetes 2009; 58(2):469-477.
非專利文獻7：Zoja C, Zanchi C, Benigni A. Key pathways in renal disease progression of experimental diabetes. Nephrology, dialysis, transplantation 2015; 30(iv):54-59.
非專利文獻8：Kanamori H, Matsubara T, Mima A, et al. Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochemical and Biophysical Research Communications 2007; 360(4):772-777.
非專利文獻9：Zineh I, Beitelshees AL, Silverstein JH, et al. Serum Monocyte Chemoattractant Protein-1 Concentrations Associate With Diabetes Status but Not Arterial Stiffness in Children With Type 1 Diabetes. Diabetes Care 2009; 32(3):465-467.
非專利文獻10：de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease. The New England Journal of Medicine 2013; 369(26):2492-2503.
非專利文獻11：Heerspink HJL, Chertow GM, Akizawa T, et al. Baseline characteristics in the Bardoxolone methyl EvAluation in patients with Chronic kidney disease and type 2 diabetes mellitus: the Occurrence of renal eveNts (BEACON) trial. Nephrology, dialysis, transplantation 2013; 28(11):2841-2850.
非專利文獻12：Pergola PE, Raskin P, Toto RD, et al. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. The New England Journal of Medicine 2011; 365(4):327-336.
非專利文獻13：Zoja C, Corna D, Nava V, et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. American journal of physiology. Renal physiology 2013; 369(26):F808-819.
非專利文獻2：國際糖尿病聯盟(International Diabetes Federation)＜全球糖尿病概覽第7版＞ 2015 (http://www.diabetesatlas.org/)。
非專利文獻3：日本透析醫學會＜圖表 日本國慢性透析療法現況 2014年12月31日現今、日本透析醫學會發行2015年12月1日＞ 2015(http://www.jsdt.or.jp/overview_confirm.html)。
非專利文獻4：Kumar PA, Brosius FC, Menon R. The Glomerular Podocyte as a Target of Growth Hormone Action: Implications for the Pathogenesis of Diabetic Nephropathy. Current Diabetes Reviews 2011; 7(1):50-55.
非專利文獻5：Brosius FC, Tuttle KR, Kretzler M. JAK inhibition in the treatment of diabetic kidney disease. Diabetologia 2016; 59(8):1624-1627.
非專利文獻6：Berthier CC, Zhang H, Schin ML, et al. Enhanced Expression of Janus Kinase-Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy. Diabetes 2009; 58(2):469-477.
非專利文獻7：Zoja C, Zanchi C, Benigni A. Key pathways in renal disease progression of experimental diabetes. Nephrology, dialysis, transplantation 2015; 30(iv):54-59.
非專利文獻8：Kanamori H, Matsubara T, Mima A, et al. Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochemical and Biophysical Research Communications 2007; 360(4):772-777.
非專利文獻9：Zineh I, Beitelshees AL, Silverstein JH, et al. Serum Monocyte Chemoattractant Protein-1 Concentrations Associate With Diabetes Status but Not Arterial Stiffness in Children With Type 1 Diabetes. Diabetes Care 2009; 32(3):465-467.
非專利文獻10：de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease. The New England Journal of Medicine 2013; 369(26):2492-2503.
非專利文獻11：Heerspink HJL, Chertow GM, Akizawa T, et al. Baseline characteristics in the Bardoxolone methyl EvAluation in patients with Chronic kidney disease and type 2 diabetes mellitus: the Occurrence of renal eveNts (BEACON) trial. Nephrology, dialysis, transplantation 2013; 28(11):2841-2850.
非專利文獻12：Pergola PE, Raskin P, Toto RD, et al. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. The New England Journal of Medicine 2011; 365(4):327-336.
非專利文獻13：Zoja C, Corna D, Nava V, et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. American journal of physiology. Renal physiology 2013; 369(26):F808-819.
[發明所欲解決之課題]
本發明之目的在於提供可預防或治療糖尿病性腎病之藥劑。
[用以解決課題之手段]
[用以解決課題之手段]
因此，本發明人等根據本發明人等所發現之糖尿病性腎病之發病機制而開發糖尿病性腎病之治療藥，且發現治療藥候補物質並完成發明。
糖尿病性腎病是指因慢性高血糖狀態所造成微血管障害之一。病理學上呈腎小球體血管基底膜增厚、腎小球環間膜(mesangial cell)區擴大，臨床上呈蛋白尿(微量白蛋白尿)、高血壓、浮腫等症狀，最終多因腎小球硬化病變導致腎衰竭。又，糖尿病中，在腎小球以外的組織也觀察到小動脈硬化症、腎小管基質(renal tubulointerstitium)的變性、纖維化等異常，會使腎小球病變更為惡化。亦即，在罹患糖尿病一定期間後，蛋白尿、高血壓、腎功能障害會逐漸加重，該病態可定義為腎病。本發明人等證明TGF-β超家族系之I型受體之ALK(activing receptor-like kinase)之下游分子之核轉錄因子Smad1，為將IV型膠原蛋白(type IV collagen)α1、α2鏈基因直接轉錄活化之因子，且該等為糖尿病性腎病中腎小球之腎小球環間膜基質擴大的最重要成因分子1 、 2
。Smad1為STZ(streptozotocin，鏈佐黴素)誘發糖尿病小鼠中誘導腎小球環間膜基質擴大的最重要因子3
。又，各種研究中顯示在糖尿病動物模型中Smad1訊息路徑與其病變形成具有強關連性4-10
。
又，本發明人等發現經由BMP4(bone morphogenetic protein 4)/ALK3調控之Smad1訊息傳導路徑的活化，在糖尿病性腎病之病理學特徵之腎小球環間膜區擴大中扮演重要的角色11
。以下說明其作用機制之詳細內容。若高血糖狀態持續不墜，則血液中AGE(advanced glycation end products)會增加。接著，若該血液中的AGE結合於腎小球環間膜細胞上的AGE受體，會使腎小球環間膜細胞之BMP4的產生增加。接著，若BMP4與腎小球環間膜細胞上的ALK3受體結合，則會引起Smad1的磷酸化，而2分子的磷酸化Smad1與1分子的Smad4形成三聚物，並由細胞質轉移至細胞核內，開始標靶基因之一的IV型膠原蛋白的轉錄，而該IV型膠原蛋白產生的增加則與腎小球環間膜基質擴大相關(圖1)。
根據上述作用機制，可抑制該BMP4/ALK3/Smad1/IV型膠原蛋白路徑之化合物被認為可成為糖尿病性腎病之預防、治療藥。BMP4/ALK3為TGF-β超家族系的一員11
。近年來RAR(Retinoic acid receptor)促效劑被指出可抑制TGF-β訊息傳達12
。基於上述理由，針對各種RAR促效劑(RARγ agonist)的評價已被進行。
RAR具有三個亞型α、β、及γ。具RAR促效劑活性之化合物對於亞型具有特異性或選擇性，因此可期待減少副作用風險(專利文獻1)。其中已揭示RARα促效劑等類視色素(retinoid)或4-[(5,6,7,8-四氫-5,5,8,8-四甲基-2-萘)胺甲醯基]安息香酸(4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid)為糖尿病性視網膜病變或老化黃斑變性的預防及/或治療藥(參照專利文獻2、專利文獻3、專利文獻4)。另一方面，已證明以帕羅伐汀(Palovarotene)為代表之RARγ促效劑可用於治療肺氣腫、癌症、及皮膚疾病(專利文獻5)，且可用於治療神經性疼痛(專利文獻6)。又，專利文獻7記載帕羅伐汀可用於肌肉修復。但是至今為止帕羅伐汀對糖尿病性腎病之效果並未被檢討，也未有文獻有所教示。
另一方面，糖尿病所誘發之腎小管基質病變係TGF-β將Smad2/3磷酸化，並誘導αSMA而誘發纖維化13 、 14
。腎小管基質病變為糖尿病性腎病進展之病態之一。先前研究揭示「高血糖及隨之產生的腎小球過量過濾、或與糖尿病高頻率併發之高血壓等血流動力學異常，最終將會導致腎單位數減少，而加速腎基質之纖維化等組織學性變化，使腎衰竭進展15
」。
腎小管基質病變與腎小球病變同樣是糖尿病性腎病之重要病態之一。但是在至今為止的糖尿病性腎病預防、治療藥的探索中，幾乎未嘗試藉由同時評價腎小球與腎小管基質的病變，而探索更為有效之預防、治療藥。因此構築使用培養腎小球環間膜細胞之in vitro評價系統，以RARγ促效劑為中心探索抑制BMP4/ALK3/Smad1/IV膠原蛋白路徑或Smad2/3的磷酸化之低分子化合物，結果發現RARγ促效劑可抑制該等路徑或磷酸化，從而完成本發明。可抑制BMP4/ALK3/Smad1/IV膠原蛋白路徑或Smad2/3磷酸化之化合物可用於與糖尿病相關併發症之預防及/或治療，尤其是糖尿病性腎病之預防及/或治療。
又，近年構築腎小管基質纖維化之病灶之纖維芽細胞(至少其一部分)源自於紅血球生成素(erythropoietin ，EPO)產生細胞，在轉形至纖維芽細胞(fibroblasts)時會喪失EPO產生能力，因此可假設基質纖維化之進展與腎性貧血之進展為共通機制14 。根據該假設，基質纖維化之預防及/或治療藥應可成為有效之腎性貧血之預防及/或治療藥。
又，近年構築腎小管基質纖維化之病灶之纖維芽細胞(至少其一部分)源自於紅血球生成素(erythropoietin ，EPO)產生細胞，在轉形至纖維芽細胞(fibroblasts)時會喪失EPO產生能力，因此可假設基質纖維化之進展與腎性貧血之進展為共通機制14 。根據該假設，基質纖維化之預防及/或治療藥應可成為有效之腎性貧血之預防及/或治療藥。
本發明主旨如下。
(1)一種糖尿病性腎病之預防藥及/或治療藥，係含有RARγ促效劑(RARγ agonist)作為有效成分。
(2)如(1)所記載之預防藥及/或治療藥，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid)、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸(4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(3)如(1)所記載之預防藥及/或治療藥，其中糖尿病性腎病源自於2型糖尿病。
(4)一種腎性貧血之預防藥及/或治療藥，係含有RARγ促效劑作為有效成分。
(5)一種抑制腎小球環間膜細胞中IV型膠原蛋白的表現之藥劑，係含有RARγ促效劑作為有效成分。
(6)如(5)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸(4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(7)一種抑制腎小球環間膜細胞中BMP4的表現之藥劑，係含有RARγ促效劑作為有效成分。
(8)如(7)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(9)一種抑制腎小管基質中的纖維化之藥劑，係含有RARγ促效劑作為有效成分。
(10)如(9)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、或帕羅伐汀之酯及該等鹽所成群組所選擇之至少1種化合物。
(11)如(9)所記載之藥劑，其抑制腎小管基質細胞中pSmad2/3的表現。
(12)如(9)所記載之藥劑，其中腎小管基質中的纖維化源自於糖尿病性腎病。
(13)如(1)~(12)中任一項所記載之藥劑，其中投藥形態為經口投藥或非經口投藥。
[發明之功效]
(1)一種糖尿病性腎病之預防藥及/或治療藥，係含有RARγ促效劑(RARγ agonist)作為有效成分。
(2)如(1)所記載之預防藥及/或治療藥，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid)、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸(4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(3)如(1)所記載之預防藥及/或治療藥，其中糖尿病性腎病源自於2型糖尿病。
(4)一種腎性貧血之預防藥及/或治療藥，係含有RARγ促效劑作為有效成分。
(5)一種抑制腎小球環間膜細胞中IV型膠原蛋白的表現之藥劑，係含有RARγ促效劑作為有效成分。
(6)如(5)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸(4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(7)一種抑制腎小球環間膜細胞中BMP4的表現之藥劑，係含有RARγ促效劑作為有效成分。
(8)如(7)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid)、該等酯及該等鹽所成群組所選擇之至少1種化合物。
(9)一種抑制腎小管基質中的纖維化之藥劑，係含有RARγ促效劑作為有效成分。
(10)如(9)所記載之藥劑，其中RARγ促效劑係由帕羅伐汀(Palovarotene)、或帕羅伐汀之酯及該等鹽所成群組所選擇之至少1種化合物。
(11)如(9)所記載之藥劑，其抑制腎小管基質細胞中pSmad2/3的表現。
(12)如(9)所記載之藥劑，其中腎小管基質中的纖維化源自於糖尿病性腎病。
(13)如(1)~(12)中任一項所記載之藥劑，其中投藥形態為經口投藥或非經口投藥。
[發明之功效]
本發明之糖尿病性腎病之預防藥及/或治療藥之有效成分之RARγ促效劑，尤其是帕羅伐汀、該等酯或該等鹽可抑制腎小管基質中的纖維化，及用於糖尿病性腎病發病之預防或治療，故有可能阻止病狀惡化至需人工透析的狀態。
以下，對本發明進行詳細說明。
本發明提供含有RARγ促效劑(RARγ agonist)作為有效成分之糖尿病性腎病之預防藥及/或治療藥。
本發明提供含有RARγ促效劑(RARγ agonist)作為有效成分之糖尿病性腎病之預防藥及/或治療藥。
RARγ促效劑對BMP4/ALK3/Smad1/IV型膠原蛋白路徑有抑制作用。
本說明書中，「BMP4/ALK3/Smad1/IV型膠原蛋白路徑」是指BMP4結合於ALK3/BMPRII(BMP之II型受體)並使Smad1磷酸化而誘導IV型膠原蛋白(type IV collagen)產生之路徑16
。其具體例如以下所示：若在AGE(advanced glycation end product)存在下培養腎小球環間膜細胞(mesangial cell)，則BMP4(bone morphogenetic protein 4)的產生會增加。又，若BMP4與在腎小球環間膜細胞上之ALK3/BMPRII受體結合，則會引起Smad1的磷酸化，2分子的磷酸化Smad1與1分子的Smad4會形成三聚物並由細胞質轉移至細胞核內，開始標靶基因之一之IV型膠原蛋白的轉錄。該IV型膠原蛋白的產生已知為腎小球環間膜基質擴大之最重要因素，故該抑制BMP4/ALK3/Smad1/IV型膠原蛋白路徑之化合物認為可成為糖尿病性腎病之預防、治療藥。因此，本發明提供一種含有RARγ促效劑作為有效成分並可抑制腎小球環間膜細胞中IV型膠原蛋白的表現的藥劑。又，本發明亦提供一種含有RARγ促效劑作為有效成分並可抑制腎小球環間膜細胞中BMP4的表現的藥劑。
又，本發明提供一種含有RARγ促效劑作為有效成分並可用於預防及/或治療糖尿病性腎病，尤其糖尿病所誘發腎小管基質(renal tubulointerstitium)病變(尤其是纖維化)之預防及/或治療藥。
RARγ促效劑對TGF-β/smad2/3 /ECM路徑之訊息有抑制作用。
本說明書中，「TGF-β/smad2/3 /ECM路徑」是指以下路徑：因高血糖或AGEs使腎小球構成細胞及腎小管構成細胞分泌TGF-β，並與TGF-β受體結合而促進Smad2/3的磷酸化，進一步誘發細胞外基質(extracellular matrix ，ECM)蛋白的過剩累積，而引起腎小管基質纖維化。Smad2/3被認為會因TGF-β刺激而磷酸化並具有作為核轉移轉錄活性因子的功能17
。因此，本發明提供一種含有RARγ促效劑作為有效成分，並可抑制腎小管基質中的纖維化的藥劑，係含有RARγ促效劑作為有效成分。該藥劑可抑制腎小管基質細胞中pSmad2/3的表現。腎小管基質中的纖維化可源自於糖尿病性腎病。
近年來，構築腎小管基質纖維化之病灶之纖維芽細胞(至少其一部分)源自於紅血球生成素(EPO)產生細胞，在轉形為纖維芽細胞時喪失EPO產生能力，因此可假設基質纖維化之進展與腎性貧血之進展為共通機制14 。根據該假設，基質纖維化之預防及/或治療藥被認為應可成為腎性貧血之有效預防及/或治療藥。因此，本發明亦提供含有RARγ促效劑作為有效成分之腎性貧血之預防藥及/或治療藥。
近年來，構築腎小管基質纖維化之病灶之纖維芽細胞(至少其一部分)源自於紅血球生成素(EPO)產生細胞，在轉形為纖維芽細胞時喪失EPO產生能力，因此可假設基質纖維化之進展與腎性貧血之進展為共通機制14 。根據該假設，基質纖維化之預防及/或治療藥被認為應可成為腎性貧血之有效預防及/或治療藥。因此，本發明亦提供含有RARγ促效劑作為有效成分之腎性貧血之預防藥及/或治療藥。
糖尿病性腎病可為源自於2型糖尿病之腎病。但本發明之範圍並不限定於該等。本發明可適用於各類型糖尿病性腎病之預防及/或治療。
本發明之RARγ促效劑可舉例如下式(I)所示：
4-[(E)-2-[5,5,8,8-四甲基-3-(吡唑-1-基-甲基)-6,7-二氫萘-2-基]乙烯基]苯甲酸 (英文化學式：4-[(E)-2-[5,5,8,8-Tetramethyl-3-(pyrazol-1-ylmethyl)-6,7-dihydronaphthalen-2-yl]ethenyl]benzoic acid)，又稱為 帕羅伐汀(Palovarotene)、
下式(II)所示：
6-[3-(1-金剛烷)-4-羥基苯基]-2-萘羧酸 (英文化學式： 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid，又稱為O-去甲基阿達巴林 (O-Desmethyl Adapalene)、
下式(III)所示：
3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(英文化學式：3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid )，又稱為BMS189961、
下式(IV)所示：
4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸 (英文化學式：4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid )，又稱為CD1530、
以及該等化合物(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)之酯、及該等化合物(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)之鹽等。
4-[(E)-2-[5,5,8,8-四甲基-3-(吡唑-1-基-甲基)-6,7-二氫萘-2-基]乙烯基]苯甲酸 (英文化學式：4-[(E)-2-[5,5,8,8-Tetramethyl-3-(pyrazol-1-ylmethyl)-6,7-dihydronaphthalen-2-yl]ethenyl]benzoic acid)，又稱為 帕羅伐汀(Palovarotene)、
下式(II)所示：
6-[3-(1-金剛烷)-4-羥基苯基]-2-萘羧酸 (英文化學式： 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid，又稱為O-去甲基阿達巴林 (O-Desmethyl Adapalene)、
下式(III)所示：
3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸(英文化學式：3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid )，又稱為BMS189961、
下式(IV)所示：
4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸 (英文化學式：4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid )，又稱為CD1530、
以及該等化合物(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)之酯、及該等化合物(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)之鹽等。
[化1]
帕羅伐汀(Palovarotene)
帕羅伐汀(Palovarotene)
[化2]
O-去甲基阿達巴林(O-Desmethyl Adapalene)
O-去甲基阿達巴林(O-Desmethyl Adapalene)
[化3]
BMS189961
BMS189961
[化4]
CD1530
CD1530
又，本發明之其他態樣可舉出：將RARγ促效劑投藥於對象作爲特徵之糖尿病性腎病之預防及/或治療方法、用以使用作為糖尿病性腎病之預防藥及/或治療藥之RARγ促效劑、RARγ促效劑在糖尿病性腎病之預防藥及/或治療藥調製中的使用。
本發明之又一其他態樣可舉出：將RARγ促效劑投藥於對象作爲特徵之腎性貧血之預防及/或治療方法、用以使用作為腎性貧血之預防藥及/或治療藥之RARγ促效劑、RARγ促效劑在腎性貧血之預防藥及/或治療藥之調製中的使用。
本發明之又一其他態樣可舉出：將RARγ促效劑投藥於對象作爲特徵之腎性貧血之預防及/或治療方法、用以使用作為腎性貧血之預防藥及/或治療藥之RARγ促效劑、RARγ促效劑在腎性貧血之預防藥及/或治療藥之調製中的使用。
本發明之糖尿病性腎病及/或腎性貧血之預防藥及/或治療藥之有效成分，其中帕羅伐汀為專利文獻5所記載之公知化合物，O-去甲基阿達巴林為以下文獻(Sun SY. et al., Cancer Research (2002))18
及專利文獻8所記載之公知化合物，BMS189961為專利文獻8所記載之公知化合物，CD1530為以下文獻(Shimono K. et al., Nat Med. 17(4): 454-460(2011))19
所記載之公知化合物，該等化合物、其酯或其鹽可根據常法製造，此外可購入市售品。後述實施例所使用帕羅伐汀係由Toronto公司購入，O-去甲基阿達巴林係由Toronto公司購入，BMS189961係由Axon Medchem公司購入，CD1530係由ApexBio公司購入。
本發明之糖尿病性腎病及/或腎性貧血之預防藥及/或治療藥之有效成分之RARγ促效劑之酯中，酯只要是活體內在生理條件下因酵素等反應而轉換為RARγ促效劑之酯，則無特別限制，如此酯可舉出與甲醇、乙醇、丙醇、己醇或十二醇等一級醇的酯；與異丙醇、第二丁醇或1-乙基丙醇等二級醇的酯；與第三丁醇或1-甲基-1-乙基丙醇等三級醇的酯；或與2-胺基乙醇等胺基醇的酯等。
上述酯可由公知方法由RARγ促效劑或其合成中間物而製造。
本發明之糖尿病性腎病及/或腎性貧血之預防藥及/或治療藥之有效成分之RARγ促效劑之鹽中，鹽只要是醫藥上容許的鹽，則無特別限制，如此鹽可舉出：(1)作為酸加成鹽有鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸鹽或磷酸鹽等無機酸鹽；或乙酸鹽、三氟乙酸鹽、安息香酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、馬來酸鹽、延胡索酸鹽、酒石酸鹽、檸檬酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、三氟甲烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、麩胺酸鹽或天冬胺酸鹽等有機酸鹽；或(2)作為鹼性鹽有鈉鹽、鉀鹽、鈣鹽或鎂鹽等金屬鹽；銨鹽等無機鹽；或三乙胺鹽或胍鹽等有機胺鹽等。
本發明之糖尿病性腎病及/或腎性貧血之預防藥及/或治療藥可與適宜藥理學上容許的添加劑混合而製造，可以錠劑、膠囊劑、散劑、糖漿劑、顆粒劑、細粒劑、丸劑、液劑、懸濁劑、乳劑、經皮吸收劑、栓劑、軟膏劑、乳液、吸入劑或注射劑等形態以經口或非經口(靜脈內投藥、肌肉內投藥、腹腔內投藥、經皮投藥、經呼吸道投藥、皮內投藥或皮下投藥)而投藥。例如用於經口投藥之組成物可舉出固體或液體之劑形，具體而言可舉出錠劑(包括糖衣錠、膜衣錠)、丸劑、顆粒劑、散劑、膠囊劑(包括軟膠囊劑)、糖漿劑、乳劑、懸濁劑等。該組成物可由常法製造，也可含有製劑領域中一般使用之擔體、稀釋劑或賦形劑。例如作為錠劑用擔體，賦形劑可舉出乳糖、澱粉、蔗糖、硬脂酸鎂等。
用於非經口投藥之組成物可舉例如注射劑、栓劑等，注射劑可為靜脈注射劑、皮下注射劑、皮內注射劑、肌肉注射劑、點滴注射劑等劑型。該注射劑係藉由常法，亦即藉由將RARγ促效劑溶解、懸濁或乳化於一般注射劑所使用之無菌水性或油性液而調製。注射用水性液可舉出含有生理食鹽水、葡萄糖或其他補助藥之等張溶液等，可併用適當溶解補助劑，例如醇(例如乙醇)、多元醇(例如丙二醇、聚乙二醇)、非離子界面活性劑(例如聚山梨醇酯80、HCO-50(polyoxyethylene (50mol) adduct of hydrogenated castor oil))等。油性液可舉出芝麻油、大豆油等，可併用作為溶解補助劑之安息香酸苄酯、苄醇等。所調製注射液一般充填於適當安瓿。可將具有Smad1表現抑制作用之物質混合於一般栓劑用基劑，藉此調製直腸投藥所使用之栓劑。
上述經口用或非經口用醫藥組成物可以適合於有效成分投藥量之方式調製為投藥單位之劑形。該投藥單位之劑形可舉出錠劑、丸劑、膠囊劑、注射劑(安瓿)、栓劑等。
該等製劑可使用賦形劑、滑潤劑、結合劑、崩壞劑、乳化劑、安定劑、矯味矯臭劑或稀釋劑等添加劑以公知方法製造。
賦形劑可舉例如有機系賦形劑或無機系賦形劑。有機系賦形劑可舉例如乳糖、蔗糖、葡萄糖、甘露醇或山梨醇等糖衍生物；玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精等澱粉衍生物；結晶纖維素等纖維素衍生物；***膠；聚葡萄醣；或聚三葡萄糖等。無機系賦形劑可舉例如輕質無水矽酸；或硫酸鈣等硫酸鹽等。
滑潤劑可舉例如硬脂酸；硬脂酸鈣或硬脂酸鎂等硬脂酸金屬鹽；滑石；膠體二氧化矽；蜂蠟或鯨蠟等蠟類；硼酸；己二酸；硫酸鈉等硫酸鹽；乙二醇；延胡索酸；安息香酸鈉；D,L-白胺酸；月桂基硫酸鈉；無水矽酸或矽酸水合物等矽酸類；或上述賦形劑中的澱粉衍生物等。
結合劑可舉例如羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯吡咯啶酮、聚乙烯二醇（MACROGOL）或上述賦形劑所示之化合物等。
崩壞劑可舉例如低取代羥丙纖維素、羧甲基纖維素、羧甲基纖維素鈣或內部交聯羧甲基纖維素鈣等纖維素衍生物；交聯聚乙烯吡咯啶酮；或羧甲基澱粉或羧甲基澱粉鈉等經化學修飾之澱粉或纖維素衍生物等。
乳化劑可舉例如膨土或矽酸鎂鋁（VEEGUM）等膠體性黏土；月桂基硫酸鈉等陰離子界面活性劑；氯化苄烷銨等陽離子界面活性劑；或聚氧乙烯烷基醚、聚氧乙烯山梨醇酐脂肪酸酯或蔗糖脂肪酸酯等非離子界面活性劑等。
安定劑可舉例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯等對羥基安息香酸酯類；氯丁醇、苄醇或苯基乙醇等醇類；氯化苄烷銨；苯酚或甲酚等苯酚類；乙汞硫柳酸鈉；乙酸酐；或山梨酸。
矯味矯臭劑可舉例如糖精鈉或阿斯巴甜等甜味料；檸檬酸、蘋果酸或酒石酸等酸味料；或薄荷醇、檸檬萃取物或橘萃取物等香料等。
稀釋劑為一般使用作為稀釋劑之化合物，可舉例如乳糖、甘露醇、葡萄糖、蔗糖、硫酸鈣、羥基丙基纖維素、微晶性纖維素、水、乙醇、聚乙二醇、丙二醇、甘油、澱粉、聚乙烯吡咯啶酮或該等之混合物等。
本發明之糖尿病性腎病及/或腎性貧血之預防或治療藥之投藥量可因應劑型、欲投藥患者之症狀輕重、年齡、體重、醫師判斷等而適宜變更，經口劑的情形一般對成人為每1天換算為有效成分量為0.01~5000mg，較佳為0.1~2500mg，更佳為0.5~1000mg，可一次性投藥或分為數次投藥。
本發明之糖尿病性腎病及/或腎性貧血之預防藥及/或治療藥只要以RARγ促效劑為有效成分，則無特別限制。以帕羅伐汀為代表之RARγ促效劑係抑制TGF-β、BMP4、Col4α1的表現，故期待可抑制腎小球環間膜基質擴大。
根據上述作用機制，可抑制BMP4/ALK3/Smad1/IV型膠原蛋白路徑或TGF-β/smad2/3 /ECM路徑之化合物、蛋白質等阻礙劑係預測可具有與帕羅伐汀類似之效果。例如Zhang等人證明Noggin可抑制糖尿病小鼠之BMP4的表現20
。Maciel等人表示GREM1可抑制BMP4活性21
。Yu等人表示Dorsomorphin可抑制BMP4所誘導Smad1磷酸化，進而證明Dorsomorphin可抑制BMP4訊息傳達路徑相關標靶ALK3或Smad122
。Yu等人教示經最佳化之分子LDN-193189可抑制透過BMP4之Smad1與ALK3的轉錄活性23
。Xu人等證明使Calmodulin與Smad1之N-terminal domain作用而可抑制Smad1的活性24
。其他研究亦表示Smad6可抑制Smad1關連之Runx1活性，進而抑制BMP4訊息傳達路徑25
。另一方面，先前研究教示Chondroitin-4-sulfate(C4S)可抑制IV型膠原蛋白的分解26
。其他阻礙物質，例如Neely等人教示DMH-1可取代Noggin並抑制ALK327
，ΔSmad73TEVGR可抑制Smad1的磷酸化28
。BMP4/ALK3/Smad1/IV型膠原蛋白路徑相關之重要標靶分子之BMP4、ALK3、Smad1及IV型膠原蛋白之阻礙劑等統整於表1。
表1. BMP4/ALK3/Smad1/IV型膠原蛋白路徑之相關訊息之阻礙劑一覽
另一方面，Bourgeois等人表示MAN1之過剩表現會誘導Smad2及Smad3的脫磷酸化29
。TGF-β/smad2/3 /ECM路徑之阻礙劑等統整於表2。
表2. TGF-β/smad2/3 /ECM路徑之阻礙劑一覽
不僅限於上述阻礙劑、分子、訊息，可阻礙BMP4/ALK3/Smad1/IV型膠原蛋白路徑或TGF-β/smad2/3 /ECM路徑之物質係被認為與本發明有相同效果。
(實施例)
(實施例)
以下藉由實施例對本發明具體地說明。又，本發明之範圍並不以該等實施例為限。
〔實施例1〕
＜帕羅伐汀對於小鼠腎小球環間膜細胞的作用檢討＞
(方法)
由4週大之野生型C57BL/6J小鼠根據Davies M人等之方法(Kidney Int. 1994;45(2):320-7)36 單離腎小球並進行初期培養，而確立小鼠腎小球環間膜細胞株。細胞刺激所使用之AGE係根據Doi T人等之方法(Proc, Nalt. Acad. Sci. U.S.A. 1992; 89:2873-2877)37 而製備。
使小鼠腎小球環間膜培養細胞增殖至匯合(confluence)，於Opti-MEM(Invitrogen)進行血清飢餓(serum starvation)，(1)無刺激條件、 (2) 添加AGE 300μg/mL、(3) 添加AGE 300μg/mL+帕羅伐汀0.5μM、及(4) 添加AGE 300μg/mL+帕羅伐汀1μM，24小時後以AGPC法進行RNA提取。使用該RNA進行RT-quantitative PCR，以循環比較法(ΔΔCt法)評價mRNA表現等級。評價對象基因為TGF-β1、BMP4、及Col4α1。結果示於圖2。
＜帕羅伐汀對於小鼠腎小球環間膜細胞的作用檢討＞
(方法)
由4週大之野生型C57BL/6J小鼠根據Davies M人等之方法(Kidney Int. 1994;45(2):320-7)36 單離腎小球並進行初期培養，而確立小鼠腎小球環間膜細胞株。細胞刺激所使用之AGE係根據Doi T人等之方法(Proc, Nalt. Acad. Sci. U.S.A. 1992; 89:2873-2877)37 而製備。
使小鼠腎小球環間膜培養細胞增殖至匯合(confluence)，於Opti-MEM(Invitrogen)進行血清飢餓(serum starvation)，(1)無刺激條件、 (2) 添加AGE 300μg/mL、(3) 添加AGE 300μg/mL+帕羅伐汀0.5μM、及(4) 添加AGE 300μg/mL+帕羅伐汀1μM，24小時後以AGPC法進行RNA提取。使用該RNA進行RT-quantitative PCR，以循環比較法(ΔΔCt法)評價mRNA表現等級。評價對象基因為TGF-β1、BMP4、及Col4α1。結果示於圖2。
(結果)
根據RAR促效劑可抑制TGF-β訊息傳達之習知知識，首先檢討帕羅伐汀是否會抑制因AGE刺激之TGF-β表現，如圖2A所示，因AGE刺激而被促進表現之TGF-β的表現被帕羅伐汀顯得抑制。
接著，根據因AGE刺激會使腎小球環間膜細胞之BMP4表現增加之習知知識，檢討帕羅伐汀對於BMP4表現的作用，如圖2B所示，帕羅伐汀係對因AGE刺激而增加之BMP4之表現有著用量依存的抑制關係，且在以1μM之濃度處理下BMP4的增加幾乎被完全抑制。
又，檢討帕羅伐汀相對於腎小球環間膜區擴大之原因因子之Col4α1(IV型膠原蛋白)表現的作用，發現在0.5μM之濃度處理下，因AGE刺激而增加之Col4α1(IV型膠原蛋白)的產生被完全抑制(圖2C)。
以上結果教示以下可能性：帕羅伐汀透過抑制BMP4的表現，而可抑制透過BMP4/ALK3路徑調控之IV型膠原蛋白的表現。
因此，為了進一步檢討該可能性，本發明使用糖尿病模型小鼠進行對帕羅伐汀評價。
根據RAR促效劑可抑制TGF-β訊息傳達之習知知識，首先檢討帕羅伐汀是否會抑制因AGE刺激之TGF-β表現，如圖2A所示，因AGE刺激而被促進表現之TGF-β的表現被帕羅伐汀顯得抑制。
接著，根據因AGE刺激會使腎小球環間膜細胞之BMP4表現增加之習知知識，檢討帕羅伐汀對於BMP4表現的作用，如圖2B所示，帕羅伐汀係對因AGE刺激而增加之BMP4之表現有著用量依存的抑制關係，且在以1μM之濃度處理下BMP4的增加幾乎被完全抑制。
又，檢討帕羅伐汀相對於腎小球環間膜區擴大之原因因子之Col4α1(IV型膠原蛋白)表現的作用，發現在0.5μM之濃度處理下，因AGE刺激而增加之Col4α1(IV型膠原蛋白)的產生被完全抑制(圖2C)。
以上結果教示以下可能性：帕羅伐汀透過抑制BMP4的表現，而可抑制透過BMP4/ALK3路徑調控之IV型膠原蛋白的表現。
因此，為了進一步檢討該可能性，本發明使用糖尿病模型小鼠進行對帕羅伐汀評價。
〔實施例2〕
＜帕羅伐汀對於STZ誘發糖尿病小鼠的作用檢討＞
(方法)
於12~15週大之ICR小鼠(由日本CLEA公司購入)以每1次為50mg/kg之鏈佐黴素(Wako)進行連續5天之腹腔內投藥(I.P.)，而引發糖尿病。投藥鏈佐黴素4週後，切換至高脂肪食HFD60(東方酵母工業公司)，並將帕羅伐汀以60μg/kg開始一週2次之腹腔內投藥，並於12週後解剖並進行組織學評價。結果示於圖3。
＜帕羅伐汀對於STZ誘發糖尿病小鼠的作用檢討＞
(方法)
於12~15週大之ICR小鼠(由日本CLEA公司購入)以每1次為50mg/kg之鏈佐黴素(Wako)進行連續5天之腹腔內投藥(I.P.)，而引發糖尿病。投藥鏈佐黴素4週後，切換至高脂肪食HFD60(東方酵母工業公司)，並將帕羅伐汀以60μg/kg開始一週2次之腹腔內投藥，並於12週後解剖並進行組織學評價。結果示於圖3。
(結果)
如圖3所示，與對照組小鼠(Ctrl)相比，投藥鏈佐黴素之糖尿病小鼠(DM)上觀察到腎小球之腎小球環間膜區擴大(PAS染色)、Smad1之活化(pSmad1)、Smad2/3之活化(pSmad2/3)、及IV型膠原蛋白(Col4)表現增加。又，觀察到腎小球足細胞之細胞間接合分子腎病蛋白的表現區降低(Nephrin)、及於足細胞細胞核表現的WT1減少(WT1)。以上結果表示：投藥鏈佐黴素之糖尿病小鼠係能充分反映人類糖尿病性腎病之病理組織學上變化之優異模型小鼠。
接著，與糖尿病小鼠(DM)相比，於糖尿病小鼠投予帕羅伐汀(DM+Palo)時，觀察到腎小球之腎小球環間膜區擴大被抑制(PAS染色)、抑制Smad1活化(pSmad1) 被抑制、及降低IV型膠原蛋白表現(Col4)。又，觀察到腎病蛋白的表現區降低的情形被抑制(Nephrin)、及於足細胞細胞核表現的WT1減少的情形亦被抑制(WT1)。
又，與糖尿病小鼠(DM)相比，發現於糖尿病小鼠投予帕羅伐汀(DM+Palo)時Smad2/3的磷酸化被顯著抑制。Smad2/3之活化係使因糖尿病所引發之腎小管基質病變進展之重要因子。根據抑制Smad2/3的磷酸化之結果，顯示帕羅伐汀可抑制腎小管基質纖維化。基於此，帕羅伐汀相對於糖尿病性腎病之預防或治療能力如下：抑制腎小球中Smad1的磷酸化並抑制腎小球硬化病變、抑制基質中Smad2/3的磷酸化並抑制基質纖維化。
〔實施例3〕
＜帕羅伐汀對於腎臓腎小管基質纖維化模型之單側尿管結紮(UUO)小鼠的效果＞
(方法)
單側尿管結紮(UUO：unilateral ureter obstruction)模型係在尿管結紮狀態下飼養7天並引發腎臓基質纖維化之模型。亦即，藉由單側背部切開使腎臓露出於腹膜外，此用縫合線以1mm間隔進行2~3處尿管結紮，使腎血流量及腎小球過濾率因尿管結紮而降低。又，此外，巨噬細胞浸潤於腎小管間質(tubulointerstitium)中，腎小管上皮細胞凋亡的發生，以及在間質中纖維芽細胞及細胞外基質蛋白增加，導致基質纖維化。該模型係在短期間引發纖維化且不使用毒物，故為不引發***之高再現性基質纖維化模型。使用10~12週大之ICR小鼠(由日本CLEA公司購入)建立UUO模型。對照組係未進行尿管結紮之小鼠。UUO組係在尿管結紮狀態下飼養7天而引發腎臓基質纖維化之小鼠。帕羅伐汀組係在UUO處置1天後將帕羅伐汀以1mg/kg進行連續6天之腹腔內投藥之小鼠。各組小鼠在UUO處置7天後解剖，以天狼星紅染色實施腎臓之組織學評價。各組之典型組織染色結果(各組2切片)示於圖4。
(結果)
如圖4所示，對照組小鼠之腎臓中完全未觀察到腎小管基質纖維化。尿管結紮後經過7天之UUO小鼠之腎臓中，腎小管基質被天狼星紅非常強烈地染色，可知腎小管基質有顯著纖維化。接著，於UUO小鼠投藥6天帕羅伐汀(UUO+Palo)，與UUO小鼠之腎臓組織相比，腎小管基質之天狼星紅染色程度明顯較輕，可知帕羅伐汀顯著抑制腎小管基質纖維化。
構築腎小管基質纖維化之病灶之纖維芽細胞源自於EPO產生細胞，根據轉形至纖維芽細胞時會喪失EPO產生能力之假設14 ，認為帕羅伐汀不僅為腎小管基質纖維化之預防及/或治療藥，也可成為腎性貧血之有效預防及/或治療藥。
如圖3所示，與對照組小鼠(Ctrl)相比，投藥鏈佐黴素之糖尿病小鼠(DM)上觀察到腎小球之腎小球環間膜區擴大(PAS染色)、Smad1之活化(pSmad1)、Smad2/3之活化(pSmad2/3)、及IV型膠原蛋白(Col4)表現增加。又，觀察到腎小球足細胞之細胞間接合分子腎病蛋白的表現區降低(Nephrin)、及於足細胞細胞核表現的WT1減少(WT1)。以上結果表示：投藥鏈佐黴素之糖尿病小鼠係能充分反映人類糖尿病性腎病之病理組織學上變化之優異模型小鼠。
接著，與糖尿病小鼠(DM)相比，於糖尿病小鼠投予帕羅伐汀(DM+Palo)時，觀察到腎小球之腎小球環間膜區擴大被抑制(PAS染色)、抑制Smad1活化(pSmad1) 被抑制、及降低IV型膠原蛋白表現(Col4)。又，觀察到腎病蛋白的表現區降低的情形被抑制(Nephrin)、及於足細胞細胞核表現的WT1減少的情形亦被抑制(WT1)。
又，與糖尿病小鼠(DM)相比，發現於糖尿病小鼠投予帕羅伐汀(DM+Palo)時Smad2/3的磷酸化被顯著抑制。Smad2/3之活化係使因糖尿病所引發之腎小管基質病變進展之重要因子。根據抑制Smad2/3的磷酸化之結果，顯示帕羅伐汀可抑制腎小管基質纖維化。基於此，帕羅伐汀相對於糖尿病性腎病之預防或治療能力如下：抑制腎小球中Smad1的磷酸化並抑制腎小球硬化病變、抑制基質中Smad2/3的磷酸化並抑制基質纖維化。
〔實施例3〕
＜帕羅伐汀對於腎臓腎小管基質纖維化模型之單側尿管結紮(UUO)小鼠的效果＞
(方法)
單側尿管結紮(UUO：unilateral ureter obstruction)模型係在尿管結紮狀態下飼養7天並引發腎臓基質纖維化之模型。亦即，藉由單側背部切開使腎臓露出於腹膜外，此用縫合線以1mm間隔進行2~3處尿管結紮，使腎血流量及腎小球過濾率因尿管結紮而降低。又，此外，巨噬細胞浸潤於腎小管間質(tubulointerstitium)中，腎小管上皮細胞凋亡的發生，以及在間質中纖維芽細胞及細胞外基質蛋白增加，導致基質纖維化。該模型係在短期間引發纖維化且不使用毒物，故為不引發***之高再現性基質纖維化模型。使用10~12週大之ICR小鼠(由日本CLEA公司購入)建立UUO模型。對照組係未進行尿管結紮之小鼠。UUO組係在尿管結紮狀態下飼養7天而引發腎臓基質纖維化之小鼠。帕羅伐汀組係在UUO處置1天後將帕羅伐汀以1mg/kg進行連續6天之腹腔內投藥之小鼠。各組小鼠在UUO處置7天後解剖，以天狼星紅染色實施腎臓之組織學評價。各組之典型組織染色結果(各組2切片)示於圖4。
(結果)
如圖4所示，對照組小鼠之腎臓中完全未觀察到腎小管基質纖維化。尿管結紮後經過7天之UUO小鼠之腎臓中，腎小管基質被天狼星紅非常強烈地染色，可知腎小管基質有顯著纖維化。接著，於UUO小鼠投藥6天帕羅伐汀(UUO+Palo)，與UUO小鼠之腎臓組織相比，腎小管基質之天狼星紅染色程度明顯較輕，可知帕羅伐汀顯著抑制腎小管基質纖維化。
構築腎小管基質纖維化之病灶之纖維芽細胞源自於EPO產生細胞，根據轉形至纖維芽細胞時會喪失EPO產生能力之假設14 ，認為帕羅伐汀不僅為腎小管基質纖維化之預防及/或治療藥，也可成為腎性貧血之有效預防及/或治療藥。
〔實施例4〕
＜4種類RARγ促效劑對於小鼠腎小球環間膜細胞的作用比較＞
(方法)
根據實施例1之方法比較4種類之RARγ促效劑(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)對TGF-β1、BMP4、及Col4α1之表現抑制作用。
＜4種類RARγ促效劑對於小鼠腎小球環間膜細胞的作用比較＞
(方法)
根據實施例1之方法比較4種類之RARγ促效劑(帕羅伐汀、O-去甲基阿達巴林、BMS189961、CD1530)對TGF-β1、BMP4、及Col4α1之表現抑制作用。
(結果)
表3係以「AGE 300μg/ml+帕羅伐汀0.5μM」之値設定為100%時，其它各組的的相對値進行表示。首先檢討RARγ促效劑對TGF-β1表現之抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。CD1530亦顯示用量依存性抑制作用，但其作用較帕羅伐汀弱。相較於帕羅伐汀，O-去甲基阿達巴林及BMS189961的抑制活性較弱。
接著檢討BMP4表現抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。但其他3種化合物未顯示抑制作用。
又，檢討Col4α1(IV型膠原蛋白)表現抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。CD1530亦顯示用量依存性抑制作用，但其作用相較於帕羅伐汀較弱。另一方面，O-去甲基阿達巴林顯示用量依存性Col4α1(IV型膠原蛋白)表現促進作用。又，相較於帕羅伐汀，CD1530之抑制作用較弱。
表3係以「AGE 300μg/ml+帕羅伐汀0.5μM」之値設定為100%時，其它各組的的相對値進行表示。首先檢討RARγ促效劑對TGF-β1表現之抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。CD1530亦顯示用量依存性抑制作用，但其作用較帕羅伐汀弱。相較於帕羅伐汀，O-去甲基阿達巴林及BMS189961的抑制活性較弱。
接著檢討BMP4表現抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。但其他3種化合物未顯示抑制作用。
又，檢討Col4α1(IV型膠原蛋白)表現抑制作用，如表3所示，帕羅伐汀顯示用量依存性的抑制作用。CD1530亦顯示用量依存性抑制作用，但其作用相較於帕羅伐汀較弱。另一方面，O-去甲基阿達巴林顯示用量依存性Col4α1(IV型膠原蛋白)表現促進作用。又，相較於帕羅伐汀，CD1530之抑制作用較弱。
表3. 4種類RARγ促效劑對TGF-β1、BMP4、Col4α1產生抑制作用之比較
由以上之結果(實施例1、2、3、4)認為RARγ促效劑中，帕羅伐汀對於糖尿病性腎病進展之關連因子TGF-β、BMP4、及Col4α1(IV型膠原蛋白)展現出最強且具用量依存性之抑制效果，因此帕羅伐汀有希望作為糖尿病性腎病之預防藥或治療藥。
[引用文獻]
1. Doi T, Vlassara H, Kirstein M, Yamada Y, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation endproducts is mediated via platelet derived growth factor. Proc Natl Acad Sci USA 1992; 89:2873-2877.
2. Abe H, Matsubara T, Iehara N, et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 2004; 279:14201-14206.
3. Matsubara T, Abe H, Arai H, et al. Expression of Smad1 is directly associated with glomerulosclerosis in diabetic nephropathy. Lab Invest 2006; 86:357-68.
4. Mima A, Matsubara T, Arai H, et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006; 86:927-939.
5. Ohashi S, Abe H, Takahashi T, et al. Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. J Biol Chem 2004; 279:19816-23.
6. Takahashi T, Abe H, Arai H, et al. Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. J Biol Chem 2005; 280:7100-7106.
7. Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
8. Kishi S, Abe H, Akiyama H, et al. Sox9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. J Biol Chem 2011; 286:32162-32169.
9. Abe H, Tominaga T, Matsubara T, et al. Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1-smooth muscle α-actin (SMA) signal transduction in diabetic nephropathy. J Biol Chem 2012; 287:20430-42.
10. Matsubara T, Araki M, Abe H, et al. Bone morphogenetic protein 4 and Smad1 mediate extracellular matrix production in the development of diabetic nephropathy. Diabetes 2015, 64(8):2978-90.
11. Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
12. Pendaries V, Verrcchia F, Michel S, et al. Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner. Oncogene 2003; 22:8212-8220.
13. Khalil H, Kanisicak O, Prasad V, et al. Fibroblas-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. The journal of Clinical Investigation 2017; 127(10):3770-3783.
14. 岡田浩一 腎臓疾患と線維化 日本内科學會雜誌2015、104卷8號、1658-1664。
15. 渡邊乃梨子、草場哲郎 糖尿病性腎症 京都府立醫科大學雜誌2017、126卷10號、685-695。
16. 阿部秀齊、土井俊夫 糖尿病性腎症の發症・進展の分子病態 日本内科學會雜誌2008、97卷4號、122-128。
17. 澁谷浩司 TGF-β細胞内シグナル傳達の分子機構 化學と生物 35卷7號、477-482。
18. Sun SY et al. The synthetic retinoid CD437 selectively induces apoptosis in human lung cancer cells while sparing normal human lung epithelial cells. Cancer Research 2002; 62(8): 2430-2436.
19. Shimono K, Tung W, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-[gamma] agonists. Nature medicine 2011; 17:454-460.
20. Zhang Y, Liu J, Tian XY, et al. Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic. Arteriosclerosis, Thrombosis, and Vascular Biology 2014; 34:152-159.
21. Maciel TT, Melo RS, Schor N, et al. Gremlin promotes vascular smooth muscle cell proliferation and migration. J Mol Cell Cardiol 2008; 44:370-9.
22. Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nature Chemical Biology 2008; 4(1): 33-41.
23. Yu PB, Deng DY, Lai CS, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nature Medicine 2008; 14:1363-1369.
24. Xu RH, Lechleider RJ, Shih HM, et al. Functional Analysis of Human Smad1: Role of the Amino-Terminal Domain. Biochemical and Biophysical Research Communications 1999; 258(2): 366-373.
25. Pimanda JE, Donaldson IJ, Bruijn MFTR, et al. The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(3): 840-845.
26. Novinec M, Lenarcic B, Turk B. Cysteine cathepsin activity regulation by glycosaminoglycans. Biomed Research Intnational 2014; doi: 10.1155/2014/309718.
27. Neely MD, Litt MJ, Tidball AM, et al. DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: Comparison of PAX6 and SOX1 expression during neural induction. ACS Chemical Neuroscience 2012; 3(6):482-491.
28. Wawersik S, Evola C, Whitman M, et al. Conditional BMP inhibition in Xenopus reveals stage-specific roles for BMPs in neural and neural crest induction. Developmental Biology 2005; 277(2):425-442.
29. Bourgeois B, Gilquin B, Tellier-Lebegue C, et al. Inhibition of TGF-βsignaling at the nuclear envelope: Characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Science Signaling 2013; 6(280): ra49.
30. Li W, Wei W, Zhu S, et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009; 4(1):16-19.
31. Rena G, Bain J, Elliott M, et al. D4476, a cell permeant inhibitor of CK1, suppresses the site‐specific phosphorylation and nuclear exclusion of FOXO1a. EMBO report 2004; 5(1): 60-65
32. Sawyer JS, Andersonhttps://pubs.acs.org/doi/abs/10.1021/jm0205705 - jm0205705AF10 BD, Beight DB, et al. Synthesis and activity of new Aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. Journal of Medicinal Chemistry 2003; 46(19):3953-3956.
33. Ogawa K, Saito A, Matsui H, et al. Activin-Nodal signaling is involved in propagation of mouse embryonic stem cell. Journal of Cell Science 2007; 120: 55-65.
34. Grygielko ET, Martin WM, Tweed C, et al. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-βtype I receptor kinase in puromycin induced nephritis. The journal of pharmacology and Experimental Therapeutics 2005; 313(3): 943-951.
35. Kapoun AM, Gaspar NJ, Wang Y, et al. Transforming growth factor-βreceptor type 1 (TGFRI) kinase activity but not p38 activation is required for TGF RI-induced myofibroblast differentiation and profibrotic gene expression. Molecular Pharmacology 2006; 70(2): 518-531.
36. Davies M. The mesangial cell: A tissue culture view. Kidney International 1994; 45(2):320-327.
37. Doi T, Vlassara H, Kirstein M, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc. Nalt Acad Sci. USA. 1992; 89:2873-2877.
專利文獻1：國際公開第2014/073209號。
專利文獻2：日本再表2007/037188號公報。
專利文獻3：美國公開第20160120843號公報。
專利文獻4：國際公開第2014/188716號。
專利文獻5：國際公開第2002/028810號。
專利文獻6：國際公開第2008/057930號。
專利文獻7：美國公開第20140363402號公報。
專利文獻8：日本特開第2013-536855號公報。
(產業利用性)
[引用文獻]
1. Doi T, Vlassara H, Kirstein M, Yamada Y, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation endproducts is mediated via platelet derived growth factor. Proc Natl Acad Sci USA 1992; 89:2873-2877.
2. Abe H, Matsubara T, Iehara N, et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 2004; 279:14201-14206.
3. Matsubara T, Abe H, Arai H, et al. Expression of Smad1 is directly associated with glomerulosclerosis in diabetic nephropathy. Lab Invest 2006; 86:357-68.
4. Mima A, Matsubara T, Arai H, et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006; 86:927-939.
5. Ohashi S, Abe H, Takahashi T, et al. Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. J Biol Chem 2004; 279:19816-23.
6. Takahashi T, Abe H, Arai H, et al. Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. J Biol Chem 2005; 280:7100-7106.
7. Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
8. Kishi S, Abe H, Akiyama H, et al. Sox9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. J Biol Chem 2011; 286:32162-32169.
9. Abe H, Tominaga T, Matsubara T, et al. Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1-smooth muscle α-actin (SMA) signal transduction in diabetic nephropathy. J Biol Chem 2012; 287:20430-42.
10. Matsubara T, Araki M, Abe H, et al. Bone morphogenetic protein 4 and Smad1 mediate extracellular matrix production in the development of diabetic nephropathy. Diabetes 2015, 64(8):2978-90.
11. Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
12. Pendaries V, Verrcchia F, Michel S, et al. Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner. Oncogene 2003; 22:8212-8220.
13. Khalil H, Kanisicak O, Prasad V, et al. Fibroblas-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. The journal of Clinical Investigation 2017; 127(10):3770-3783.
14. 岡田浩一 腎臓疾患と線維化 日本内科學會雜誌2015、104卷8號、1658-1664。
15. 渡邊乃梨子、草場哲郎 糖尿病性腎症 京都府立醫科大學雜誌2017、126卷10號、685-695。
16. 阿部秀齊、土井俊夫 糖尿病性腎症の發症・進展の分子病態 日本内科學會雜誌2008、97卷4號、122-128。
17. 澁谷浩司 TGF-β細胞内シグナル傳達の分子機構 化學と生物 35卷7號、477-482。
18. Sun SY et al. The synthetic retinoid CD437 selectively induces apoptosis in human lung cancer cells while sparing normal human lung epithelial cells. Cancer Research 2002; 62(8): 2430-2436.
19. Shimono K, Tung W, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-[gamma] agonists. Nature medicine 2011; 17:454-460.
20. Zhang Y, Liu J, Tian XY, et al. Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic. Arteriosclerosis, Thrombosis, and Vascular Biology 2014; 34:152-159.
21. Maciel TT, Melo RS, Schor N, et al. Gremlin promotes vascular smooth muscle cell proliferation and migration. J Mol Cell Cardiol 2008; 44:370-9.
22. Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nature Chemical Biology 2008; 4(1): 33-41.
23. Yu PB, Deng DY, Lai CS, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nature Medicine 2008; 14:1363-1369.
24. Xu RH, Lechleider RJ, Shih HM, et al. Functional Analysis of Human Smad1: Role of the Amino-Terminal Domain. Biochemical and Biophysical Research Communications 1999; 258(2): 366-373.
25. Pimanda JE, Donaldson IJ, Bruijn MFTR, et al. The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(3): 840-845.
26. Novinec M, Lenarcic B, Turk B. Cysteine cathepsin activity regulation by glycosaminoglycans. Biomed Research Intnational 2014; doi: 10.1155/2014/309718.
27. Neely MD, Litt MJ, Tidball AM, et al. DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: Comparison of PAX6 and SOX1 expression during neural induction. ACS Chemical Neuroscience 2012; 3(6):482-491.
28. Wawersik S, Evola C, Whitman M, et al. Conditional BMP inhibition in Xenopus reveals stage-specific roles for BMPs in neural and neural crest induction. Developmental Biology 2005; 277(2):425-442.
29. Bourgeois B, Gilquin B, Tellier-Lebegue C, et al. Inhibition of TGF-βsignaling at the nuclear envelope: Characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Science Signaling 2013; 6(280): ra49.
30. Li W, Wei W, Zhu S, et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009; 4(1):16-19.
31. Rena G, Bain J, Elliott M, et al. D4476, a cell permeant inhibitor of CK1, suppresses the site‐specific phosphorylation and nuclear exclusion of FOXO1a. EMBO report 2004; 5(1): 60-65
32. Sawyer JS, Andersonhttps://pubs.acs.org/doi/abs/10.1021/jm0205705 - jm0205705AF10 BD, Beight DB, et al. Synthesis and activity of new Aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. Journal of Medicinal Chemistry 2003; 46(19):3953-3956.
33. Ogawa K, Saito A, Matsui H, et al. Activin-Nodal signaling is involved in propagation of mouse embryonic stem cell. Journal of Cell Science 2007; 120: 55-65.
34. Grygielko ET, Martin WM, Tweed C, et al. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-βtype I receptor kinase in puromycin induced nephritis. The journal of pharmacology and Experimental Therapeutics 2005; 313(3): 943-951.
35. Kapoun AM, Gaspar NJ, Wang Y, et al. Transforming growth factor-βreceptor type 1 (TGFRI) kinase activity but not p38 activation is required for TGF RI-induced myofibroblast differentiation and profibrotic gene expression. Molecular Pharmacology 2006; 70(2): 518-531.
36. Davies M. The mesangial cell: A tissue culture view. Kidney International 1994; 45(2):320-327.
37. Doi T, Vlassara H, Kirstein M, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc. Nalt Acad Sci. USA. 1992; 89:2873-2877.
專利文獻1：國際公開第2014/073209號。
專利文獻2：日本再表2007/037188號公報。
專利文獻3：美國公開第20160120843號公報。
專利文獻4：國際公開第2014/188716號。
專利文獻5：國際公開第2002/028810號。
專利文獻6：國際公開第2008/057930號。
專利文獻7：美國公開第20140363402號公報。
專利文獻8：日本特開第2013-536855號公報。
(產業利用性)
本發明可利用於糖尿病性腎病之預防、治療。又，本發明之糖尿病性腎病之預防藥或治療藥之有效成分之RARγ促效劑(例如帕羅伐汀)可用於抑制腎小球之腎小球環間膜擴大、抑制Smad1活化、及抑制IV型膠原蛋白。
圖1之示意圖係表示糖尿病性腎病發病之分子訊息傳導模式。
圖2A係帕羅伐汀(Palovarotene)對於以AGE刺激小鼠腎小球環間膜細胞之TGF-β產生的效果。各組：(1)無刺激條件、 (2)添加AGE 300μg/mL、(3) 添加AGE 300μg/mL+帕羅伐汀0.5μM、及(4) 添加AGE 300μg/mL+帕羅伐汀1μM，處理24小時後以AGPC法進行RNA提取。
圖2B係帕羅伐汀(Palovarotene)對於以AGE刺激小鼠腎小球環間膜細胞之BMP4產生的效果。各組：(1)無刺激條件、(2) 添加AGE 300μg/mL、(3) 添加AGE 300μg/mL+帕羅伐汀0.5μM、及(4) 添加AGE 300μg/mL+帕羅伐汀1μM，處理24小時後以AGPC法進行RNA提取。
圖2C係帕羅伐汀(Palovarotene)對於以AGE刺激小鼠腎小球環間膜細胞之IV型膠原蛋白(Col4α1)產生的效果。各組：(1)無刺激條件、 (2) 添加AGE 300μg/mL、(3) 添加AGE 300μg/mL+帕羅伐汀0.5μM、及(4) 添加AGE 300μg/mL+帕羅伐汀1μM，處理24小時後以AGPC法進行RNA提取。
圖3係帕羅伐汀(Palovarotene)對於鏈佐黴素誘發糖尿病小鼠的效果。(1)Ctrl.為對照組小鼠之組織解剖結果、(2)Palo. Ctrl.為對對照組小鼠投予帕羅伐汀後之組織解剖結果、(3)DM為投藥鏈佐黴素並引發糖尿病之小鼠之組織解剖結果、及(4)DM+Palo為對誘發糖尿病之小鼠投予帕羅伐汀後之組織解剖結果。
圖4係帕羅伐汀(Palovarotene)對於腎臓腎小管基質纖維化模型之單側尿管結紮(unilateral ureter obstruction ，UUO)小鼠的效果。Control：未經尿管結紮之小鼠其腎臓之天狼星紅(Sirius Red)染色之組織學評價結果。UUO：尿管結紮後飼養7天並引發腎小管基質纖維化之小鼠其腎臓之天狼星紅染色之組織學評價結果。UUO+Palo：尿管結紮1天後以帕羅伐汀1mg/kg於腹腔內投藥6天之小鼠其腎臓之天狼星紅染色之組織學評價結果。
Claims (13)
- 一種糖尿病性腎病之預防藥及/或治療藥，係含有RARγ促效劑作為有效成分。
- 如請求項1所記載之預防藥及/或治療藥，其中RARγ促效劑為由帕羅伐汀(Palovarotene)、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸、該等酯及該等鹽所成群組所選擇之至少1種化合物。
- 如請求項1所記載之預防藥及/或治療藥，其中糖尿病性腎病源自於2型糖尿病。
- 一種腎性貧血之預防藥及/或治療藥，係含有RARγ促效劑作為有效成分。
- 一種抑制腎小球環間膜細胞中IV型膠原蛋白的表現之藥劑，係含有RARγ促效劑作為有效成分。
- 如請求項5所記載之藥劑，其中RARγ促效劑為由帕羅伐汀、4-[7-(1-金剛烷)-6-羥基萘-2-基]苯甲酸、該等酯及該等鹽所成群組所選擇之至少1種化合物。
- 一種抑制腎小球環間膜細胞中BMP4的表現之藥劑，係含有RARγ促效劑作為有效成分。
- 如請求項7所記載之藥劑，其中RARγ促效劑為由帕羅伐汀、3-氟-4-(2-羥基-2-(5,5,8,8-四甲基-5,6,7,8,-四氫萘-2-基)乙醯胺)苯甲酸、該等酯及該等鹽所成群組所選擇之至少1種化合物。
- 一種抑制腎小管基質中的纖維化之藥劑，係含有RARγ促效劑作為有效成分。
- 如請求項9所記載之藥劑，其中RARγ促效劑為由帕羅伐汀、或帕羅伐汀之酯及該等鹽所成群組所選擇之至少1種化合物。
- 如請求項9所記載之藥劑，其抑制腎小管基質細胞中pSmad2/3的表現。
- 如請求項9所記載之藥劑，其中腎小管基質中的纖維化源自於糖尿病性腎病。
- 如請求項1~12中任一項所記載述之藥劑，其中投藥形態為經口投藥或非經口投藥。
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