3区 · 医学
Article
作者: Lin, Daniel C.-H. ; Houze, Jonathan B. ; Brown, Sean P. ; Medina, Julio C. ; Dransfield, Paul J. ; Zhu, Liusheng ; Zhang, Jane ; Swaminath, Gayathri ; Sharma, Rajiv ; Luo, Jian ; Schmitt, Mike ; Sun, Ying ; Ma, Zhihua ; Wang, Yingcai ; Tonn, George R. ; Zhuang, Run ; Guo, Qi ; Wong, Simon ; Liu, Jiwen (Jim)
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.