小分子GPR40激动剂作为抗Ⅱ型糖尿病候选药物的研究进展

Advances in Small-Molecule GPR40 Agonists for Treatment of Type 2 Diabetes Mellitus

目前治疗Ⅱ型糖尿病的主要手段依然是口服或注射降糖药物以达到控制血糖的目的.虽然已有针对不同靶点开发的多种抗Ⅱ型糖尿病药物上市,但是鉴于糖尿病治疗药物长期服用的高安全性要求以及庞大的患病人群,研发新型安全有效的抗糖尿病药物仍然是当今药物化学研究的热点.GPR40是G-蛋白偶联受体家族中的一员,激动后可以诱导葡萄糖依赖的胰岛素分泌.因为仅在血糖浓度过高时,GPR40激动剂才能促进胰岛素分泌,所以针对该靶点开发降糖药物将极大地降低目前抗糖尿病药物低血糖副作用的风险.因此,GPR40已成为抗Ⅱ型糖尿病药物研发的前沿和热门靶点,本文将围绕小分子GPR40激动剂的药效团模型,即必需的苯丙酸核心骨架及其疏水末端和连接链的结构改造,对近年来各大制药公司及研究机构报道的小分子GPR40激动剂的研发进展进行总结评述.

Currently, the majority of the chemotherapy for type 2 diabetes mellitus（T2DM） functions through glycemic control by administration of oral or injectable hypoglycemic drugs. Though a range of anti-diabetic drugs with different modes of action have been launched, there still remains a significant need for development of effective and highly safe anti-diabetic agents for the increasing diabetic population. GPR40 belongs to the GPCR family and the activation of GPR40 can amplify glucose-stimulated insulin secretion（GSIS）. Due to the advantage of minimizing the hypoglycemia risk, GPR40 has drawn more and more attention and emerged as a promising new target for T2 DM treatment. Therefore, the recent progress on the structural optimization and further development of small molecule GPR40 agonists as novel treatment for T2 DM is reviewed, focused on those under clinical trials or at preclinical stage. A variety of small molecule GPR40 agonists were summarized from the literature and patents based on the pharmacophore model, including the critical phenylpropanoic acid core, the hydrophobic terminus and the linker. The structural features and advantage of different sources of GPR40 agonists were analyzed and highlighted.