Optimization of GPR40 Agonists for Type 2 Diabetes

  • ACS Med Chem Lett. 2014 Feb 6;5(5):517-21. doi: 10.1021/ml400501x.
Jiwen Jim Liu  1 ,  Yingcai Wang  1 ,  Zhihua Ma  1 ,  Mike Schmitt  1 ,  Liusheng Zhu  1 ,  Sean P Brown  1 ,  Paul J Dransfield  1 ,  Ying Sun  1 ,  Rajiv Sharma  1 ,  Qi Guo  1 ,  Run Zhuang  1 ,  Jane Zhang  1 ,  Jian Luo  1 ,  George R Tonn  1 ,  Simon Wong  1 ,  Gayathri Swaminath  1 ,  Julio C Medina  1 ,  Daniel C-H Lin  1 ,  Jonathan B Houze  1
Affiliations
  • 1. Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
PMID: 24900872 DOI: 10.1021/ml400501x
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.

Keywords
FFA1; FFAR1; GPCR; GPR40; agonist; insulin secretagogue; type II diabetes.
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