Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists
ACS Medicinal Chemistry Letters2014Vol. 5(4), pp. 384–389
Citations Over TimeTop 14% of 2014 papers
Xiaohui Du, Paul J. Dransfield, Daniel C.-H. Lin, Simon Wong, Yingcai Wang, Zhongyu Wang, Todd J. Kohn, Ming Yu, Sean P. Brown, Marc Vimolratana, Liusheng Zhu, An‐Rong Li, Yongli Su, Xian‐Yun Jiao, Jiwen Liu, Gayathri Swaminath, Thanhvien Tran, Jian Luo, Run Zhuang, Jane Zhang, Qi Guo, Frank Li, Richard Connors, Julio C. Medina, Jonathan B. Houze
Abstract
We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.
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