期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 9, 页码 726-730出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml300133f
关键词
GPR40; full agonist; AM-1638; AMG 837; insulin secretagogue; FFA1
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.
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