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

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journal contribution
posted on 2008-09-11, 00:00 authored by 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, Stuart Bossie, Chris Carroll, Zhi-Liang Chu, Andrew J. Grottick, Erin K. Hauser, James Leonard, Robert M. Jones
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.