用于开发新型GPR40激动剂的吲哚-5-丙酸衍生物的构效关系研究
SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists.
作者信息
Yoon Dong-Oh, Zhao Xiaodi, Son Dohyun, Han Jung Tae, Yun Jaesook, Shin Dongyun, Park Hyun-Ju
机构信息
School of Pharmacy and Department of Chemistry, Sungkyunkwan University, Suwon 16419, South Korea.
College of Pharmacy, Gachon University, Incheon 21936, South Korea.
出版信息
ACS Med Chem Lett. 2017 Nov 21;8(12):1336-1340. doi: 10.1021/acsmedchemlett.7b00460. eCollection 2017 Dec 14.
Abstract
G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, (EC = 58.6 nM), (EC = 37.8 nM), and (EC = 9.4 nM), were identified as potent GPR40 agonists with good GSIS effects.
摘要
G蛋白偶联受体40（GPR40）因其在游离脂肪酸介导的增强胰腺β细胞葡萄糖刺激的胰岛素分泌（GSIS）中所起的作用，而被认为是治疗2型糖尿病的一个有吸引力的药物靶点。合成了一系列吲哚-5-丙酸化合物，并通过活化T细胞核因子报告基因检测法和MIN-6胰岛素瘤细胞中的GSIS检测法评估了它们的GPR40激动活性。三种化合物，（EC = 58.6 nM）、（EC = 37.8 nM）和（EC = 9.4 nM），被鉴定为具有良好GSIS效应的强效GPR40激动剂。
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