Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Sean P. Brown, Paul Dransfield, Marc Vimolratana, Liusheng Zhu, Jian Luo, Jane Zhang, Xianyun Jiao, Vatee Pattaropong, Simon Wong, Run Zhuang, Gayathri Swaminath, Jonathan B. Houze, Daniel C.H. Lin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

Original languageEnglish (US)
Pages (from-to)757-760
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume9
Issue number7
DOIs
StatePublished - Jul 12 2018
Externally publishedYes

Keywords

  • AM-1638
  • AM-6226
  • AMG 837
  • FFA1
  • full agonist
  • GPR40
  • insulin secretagogue

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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