Publication in detail

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

Optimization of GPR40 Agonists for Type 2 Diabetes

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

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

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.

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