Optimization of GPR40 Agonists for Type 2 Diabetes

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ACS Med. Chem. Lett. 2014, 5 (5), pp 517–521

Optimization of GPR40 Agonists for Type 2 Diabetes

JJ Liu;Y Wang;Z Ma;M Schmitt;L Zhu;SP Brown; PJ Dransfield;Y Sun;R Sharma;Q Guo;R Zhuang;J Zhang;J Luo;GR Tonn;S Wong;G Swaminath;JC Medina;DCH Lin;JB Houze

Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States

Service type: Knock-in mice


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.

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