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

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 (<b>1</b>), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist <b>1</b> to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (<b>21</b>). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist <b>21</b> exhibits in BDF/DIO mice as compared to partial agonist <b>1</b>