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

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

  • ACS Med Chem Lett. 2018 Jun 6;9(7):757-760. doi: 10.1021/acsmedchemlett.8b00213.
Sean P Brown 1,  Paul Dransfield 1,  Marc Vimolratana 1,  Liusheng Zhu 1,  Jian Luo 1,  Jane Zhang 1,  XianYun Jiao 1,  Vatee Pattaropong 1,  Simon Wong 1,  Run Zhuang 1,  Gayathri Swaminath 1,  Jonathan B Houze 1,  Daniel C-H Lin 1
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Amgen Discovery Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 30034614 DOI: 10.1021/acsmedchemlett.8b00213
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.

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