Discovery of the First Potent and Orally Efficacious Agonist of the Orphan G-Protein Coupled Receptor 119

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• 作者：Graeme Semple ; Beatriz Fioravanti ; Guillherme Pereira ; Imelda Calderon ; Jane Uy ; Karoline Choi ; Yifeng Xiong ; Albert Ren ; Michael Morgan ; Vibha Dave ; William Thomsen ; David J. Unett ; Charles Xing ; Stu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 11, 2008
• 年：2008
• 卷：51
• 期：17
• 页码：5172-5175
• 全文大小：110K
• 年卷期：v.51,no.17(September 11, 2008)
• ISSN：1520-4804

文摘

GPR119 is a rhodopsin-like GPCR expressed in pancreatic β-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.