| Literature DB >> 24900872 |
Jiwen Jim Liu1, Yingcai Wang1, Zhihua Ma1, Mike Schmitt1, Liusheng Zhu1, Sean P Brown1, Paul J Dransfield1, Ying Sun1, Rajiv Sharma1, Qi Guo1, Run Zhuang1, Jane Zhang1, Jian Luo1, George R Tonn1, Simon Wong1, Gayathri Swaminath1, Julio C Medina1, Daniel C-H Lin1, Jonathan B Houze1.
Abstract
GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.Entities:
Keywords: FFA1; FFAR1; GPCR; GPR40; agonist; insulin secretagogue; type II diabetes
Year: 2014 PMID： 24900872 PMCID： PMC4027784 DOI： 10.1021/ml400501x
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345