Document Report Card

ID: ALA2384969

Journal: ACS Med Chem Lett

Title: Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.

Authors: Wang Y, Liu JJ, Dransfield PJ, Zhu L, Wang Z, Du X, Jiao X, Su Y, Li AR, Brown SP, Kasparian A, Vimolratana M, Yu M, Pattaropong V, Houze JB, Swaminath G, Tran T, Nguyen K, Guo Q, Zhang J, Zhuang R, Li F, Miao L, Bartberger MD, Correll TL, Chow D, Wong S, Luo J, Lin DC, Medina JC.

Abstract: GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

CiteXplore: 24900707

DOI: 10.1021/ml300427u