Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination

作者：Hui Huang, Sanath K. Meegalla, James C. Lanter, Michael P. Winters, Shuyuan Zhao, James Littrell, Jenson Qi, Brian Rady, Paul S. Lee, Jianying Liu, Tonya Martin, Wing Lam, Fran Xu, Hyun Kyoon Lim, Thomas Wilde, José de Paula Silva, Monicah A. Otieno, Alessandro Pocai, Mark R. Player · 发表于：ACS Medicinal Chemistry Letters · 年份：2018 · DOI：10.1021/acsmedchemlett.8b00444 · 被引用次数：25 · 研究领域：Diabetes Treatment and Management、Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes

GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gα s -mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.