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ACS Med Chem Lett. 2012 Aug 15;3(9):726-30. doi: 10.1021/ml300133f. eCollection 2012 Sep 13.

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

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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.

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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