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

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 (<b>2</b>), a full agonist of GPR40. Herein, we present further structure–activity relationships progressing from AM-1638 (<b>2</b>) to AM-6226 (<b>14</b>) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (<b>14</b>) 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