GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets. When activated, GPR40 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, a potent partial agonist of GPR40. Here, we present the structural optimization leading from the GPR40 partial agonist AMG 837 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638. Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist AM-1638 exhibits compared to partial agonist AMG 837.

Discovery of AM-1638: A potent and orally bioavailable GPR40 full agonist

244th National Meeting (2012)

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