Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist

  • ACS Med Chem Lett. 2012 Aug 15;3(9):726-30. doi: 10.1021/ml300133f.
Sean P Brown  1 ,  Paul J Dransfield  1 ,  Marc Vimolratana  1 ,  XianYun Jiao  1 ,  Liusheng Zhu  1 ,  Vatee Pattaropong  1 ,  Ying Sun  1 ,  Jinqian Liu  1 ,  Jian Luo  1 ,  Jane Zhang  1 ,  Simon Wong  1 ,  Run Zhuang  1 ,  Qi Guo  1 ,  Frank Li  1 ,  Julio C Medina  1 ,  Gayathri Swaminath  1 ,  Daniel C-H Lin  1 ,  Jonathan B Houze  1
Affiliations
  • 1. Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24900539 DOI: 10.1021/ml300133f
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.

Keywords
AM-1638; AMG 837; FFA1; GPR40; full agonist; insulin secretagogue.
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