新型GPR40完全激动剂的设计及其抗糖尿病结构功能研究

GPR40 (即游离脂肪酸1受体, FFA1)属于G-蛋白偶联受体，主要分布于胰岛细胞和肠分泌细胞，能够诱导葡萄糖依赖的胰岛素分泌，是当前抗II型糖尿病药物研发的热点靶标。最近由于GPR40的部分激动剂TAK-875因肝毒性而终止临床III期实验，所以靶向GPR40的安全性问题引起特别关注。我们课题组前期发现了以噻吩丙酸为核心结构的新型GPR40完全激动剂LLG-46，比TAK-875具有更高的促胰岛素分泌和体内降糖活性，并能促使GLP-1分泌。以此先导化合物为切入点，我们将开展全面的构效关系和结构优化研究，揭示GPR40完全激动剂的作用机制和药效团模型；同时，利用GPR40受体具有多个配体结合位点的变构性，以及GPR40的部分激动剂和完全激动剂作用于不同结合位点的机制，我们将设计双功能GPR40激动剂，以期提高活性和靶向选择性，降低毒副作用，发展安全有效可口服的新型抗糖尿病药物。

GPR40 (also referred to as FFAR1), belonging to the G protein-coupled receptor family, is mainly expressed in pancreatic beta cells and enteroendocrine cells and plays a major role in fatty acid amplification of glucose-induced insulin secretion. GPR40 agonists are being developed for the treatment of type 2 diabetes mellitus (T2DM) due to inducing insulin secretion in a glucose-dependent manner without the risk of iatrogenic hypoglycaemia. However, significant questions over the safety of targeting GPR40 have been recently raised following the termination of TAK-875 in phase III clinical trials because of hepatotoxicity. Recently our group has identified a new class of GPR40 full agonists bearing thiophen-2-ylpropanoic acid scaffold and displaying superior to the partial agonist TAK-875 with respect to Emax and in vivo glucose-lowering activity as well as inducing GLP-1 secretion. Starting from the lead compound LLG-46, a comprehensive SAR study and structural optimization will be performed to improve the PK property and in vivo potency and disclose the molecular mechanism and pharmacophore model of GPR40 full agonists. Meanwhile, by making use of the allosterism on GPR40, we will design chemically and structurally diverse GPR40 bitopic ligands targeting distinct allosteric sites, which may potentially circumvent the hepatotoxic effects and finally develop into an effective, safe and orally bioavailable treatment for T2DM.