Optimization of GPR40 Agonists for Type 2 Diabetes

Abstract

GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (<b>1</b>), 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 (<b>2</b>) 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 (<b>10</b>), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration