2. Academic Validation
  3. Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist

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

Affiliation

  • 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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