Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119

被引：124

作者：

Semple, Graeme ^{[1
]}

Fioravanti, Beatriz ^{[1
]}

Pereira, Guillherme ^{[1
]}

Calderon, Imelda ^{[1
]}

Uy, Jane ^{[1
]}

Choi, Karoline ^{[1
]}

Xiong, Yifeng ^{[1
]}

Ren, Albert ^{[1
]}

Morgan, Michael ^{[2
]}

Dave, Vibha ^{[3
]}

Thomsen, William ^{[3
]}

Unett, David J. ^{[3
]}

Xing, Charles ^{[3
]}

Bossie, Stuart ^{[3
]}

Carroll, Chris ^{[3
]}

Chu, Zhi-Liang ^{[3
]}

Grottick, Andrew J. ^{[3
]}

Hauser, Erin K. ^{[3
]}

Leonard, James ^{[3
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut, Dept Med Chem, San Diego, CA 92121 USA

[2] Arena Pharmaceut, Dept DMPK, San Diego, CA 92121 USA

[3] Arena Pharmaceut, Dept Discovery Biol, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 17期

关键词：

D O I：

10.1021/jm8006867

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increase,; 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.

引用

页码：5172 / 5175

页数：4

共 13 条

[1] Activation of TRPV1 by the satiety factor oleoylethanolamide [J].

Ahern, GP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (33) :30429-30434

[2] Novel cannabinoid receptors [J].

Brown, A. J. .

BRITISH JOURNAL OF PHARMACOLOGY, 2007, 152 (05) :567-575

[3] A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release [J].

Chu, Zhi-Liang ;

Carroll, Chris ;

Alfonso, Jean ;

Gutierrez, Veronica ;

He, Hongmei ;

Lucman, Annette ;

Pedraza, Melinda ;

Mondala, Helen ;

Gao, Hui ;

Bagnol, Didier ;

Chen, Ruoping ;

Jones, Robert M. ;

Behan, Dominic P. ;

Leonard, James .

ENDOCRINOLOGY, 2008, 149 (05) :2038-2047

[4] A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release [J].

Chu, Zhi-Liang ;

Jones, Robert M. ;

He, Hongmei ;

Carroll, Chris ;

Gutierrez, Veronica ;

Lucman, Annette ;

Moloney, Molly ;

Gao, Hui ;

Mondala, Helen ;

Bagnol, Didier ;

Unett, David ;

Liang, Yin ;

Demarest, Keith ;

Semple, Graeme ;

Behan, Dominic P. ;

Leonard, James .

ENDOCRINOLOGY, 2007, 148 (06) :2601-2609

[5] Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α [J].

Fu, J ;

Gaetani, S ;

Oveisi, F ;

Lo Verme, J ;

Serrano, A ;

de Fonseca, FR ;

Rosengarth, A ;

Luecke, H ;

Di Giacomo, B ;

Tarzia, G ;

Piomelli, D .

NATURE, 2003, 425 (6953) :90-93

[6] GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity [J].

Fyfe, Matthew C. T. ;

McCormack, James G. ;

Overton, Hilary A. ;

Procter, Martin J. ;

Reynet, Christine .

EXPERT OPINION ON DRUG DISCOVERY, 2008, 3 (04) :403-413

[7]

FYFE MCT, 2007, 234 ACS NAT M BOST M

[8] Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data [J].

Gallwitz, B. .

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, 2006, 60 (12) :1654-1661

[9]

JONES RM, 2004, Patent No. 200465380

[10] Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents [J].

Overton, HA ;

Babbs, AJ ;

Doel, SM ;

Fyfe, MCT ;

Gardner, LS ;

Griffin, G ;

Jackson, HC ;

Procter, MJ ;

Rasamison, CM ;

Tang-Christensen, M ;

Widdowson, PS ;

Williams, GM ;

Reynet, C .

CELL METABOLISM, 2006, 3 (03) :167-175

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