Optimization of GPR40 Agonists for Type 2 Diabetes
ACS Medicinal Chemistry Letters2014Vol. 5(5), pp. 517–521
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Jiwen Liu, Yingcai Wang, Zhihua Ma, Mike Schmitt, Liusheng Zhu, Sean P. Brown, Paul J. Dransfield, Ying Sun, Rajiv Sharma, Qi Guo, Run Zhuang, Jane Zhang, Jian Luo, George Tonn, Simon Wong, Gayathri Swaminath, Julio C. Medina, Daniel C.-H. Lin, Jonathan B. Houze
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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