Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist

Sean P. Brown, Paul J. Dransfield, Marc Vimolratana, Xianyun Jiao, Liusheng Zhu, Vatee Pattaropong, Ying Sun, Jinqian Liu, Jian Luo, Jane Zhang, Simon Wong, Run Zhuang, Qi Guo, Frank Li, Julio C. Medina, Gayathri Swaminath, Daniel C.H. Lin, Jonathan B. Houze

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

Original languageEnglish (US)
Pages (from-to)726-730
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number9
DOIs
StatePublished - Sep 13 2012
Externally publishedYes

Keywords

  • AM-1638
  • AMG 837
  • FFA1
  • full agonist
  • GPR40
  • insulin secretagogue

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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