Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

被引：14

作者：

Brocklehurst, Katy J. ^{[1
]}

Broo, Anders

Butlin, Roger J. ^{[1
]}

Brown, Hayley S. ^{[1
]}

Clarke, David S. ^{[1
]}

Davidsson, Ojvind

Goldberg, Kristin ^{[1
]}

Groombridge, Sam D. ^{[1
]}

Kelly, Elizabeth E. ^{[1
]}

Leach, Andrew ^{[1
]}

McKerrecher, Darren ^{[1
]}

O'Donnell, Charles ^{[1
]}

Poucher, Simon ^{[1
]}

Schofield, Paul ^{[1
]}

Scott, James S. ^{[1
]}

Teague, Joanne ^{[1
]}

Westgate, Leanne ^{[1
]}

Wood, Matt J. M. ^{[1
]}

机构：

[1] Mereside, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 24期

关键词：

GPR119; agonist; hERG; Knock-out mice; Transgenic animals; STIMULATED INSULIN-SECRETION; PROTEIN-COUPLED RECEPTOR; MEDICINAL CHEMISTRY; METABOLIC-DISORDERS; GLYCEMIC CONTROL; TYPE-2; POTENT; AGENTS; G-PROTEIN-COUPLED-RECEPTOR-119; AS1535907;

D O I：

10.1016/j.bmcl.2011.10.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：7310 / 7316

页数：7

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