2. Academic Validation
  3. Optimization of GPR40 Agonists for Type 2 Diabetes

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

Affiliation

  • 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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