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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 (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.

SUBMITTER: Brown SP

PROVIDER: S-EPMC4025659 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Brown Sean P SP Dransfield Paul J PJ Vimolratana Marc M Jiao XianYun X Zhu Liusheng L Pattaropong Vatee V Sun Ying Y Liu Jinqian J Luo Jian J Zhang Jane J Wong Simon S Zhuang Run R Guo Qi Q Li Frank F Medina Julio C JC Swaminath Gayathri G Lin Daniel C-H DC Houze Jonathan B JB

ACS medicinal chemistry letters 20120815 9

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 ...[more]

PMID: 24900539

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