ACS Med. Chem. Lett. 2014, 5 (5), pp 517–521
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
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.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 300 scientific publications are based on research using Ozgene mice.