Improving the pharmacokinetics of GPR40/FFA1 full agonists

Xiaohui Du, Paul J. Dransfield, Daniel C.H. Lin, Simon Wong, Yingcai Wang, Zhongyu Wang, Todd Kohn, Ming Yu, Sean P. Brown, Marc Vimolratana, Liusheng Zhu, An Rong Li, Yongli Su, Xianyun Jiao, Jiwen Liu, Gayathri Swaminath, Thanhvien Tran, Jian Luo, Run Zhuang, Jane ZhangQi Guo, Frank Li, Richard Connors, Julio C. Medina, Jonathan B. Houze

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)384-389
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number4
StatePublished - Apr 10 2014
Externally publishedYes


  • FFA1
  • GPR40
  • full agonist
  • insulin secretagoue
  • type 2 diabetes

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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