Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors

被引：46
作者：
Birch, Alan M.
Kenny, Peter W.
Oikonomakos, Nikos G.
Otterbein, Ludovic
Schofield, Paul
Whittamore, Paul R. O.
Whalley, Dave P.
机构：
[1] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England
[2] Natl Hellen Res Fdn, Inst Organ & Pharmaceut Chem, GR-11635 Athens, Greece
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 02期
关键词：
glycogen phosphorylase; glycogen phosphorylase inhibitor; 3,4-dihydro-2-quinolone; allosteric inhibitor; dimer interface; X-ray crystallography; physical properties; DMPK properties; solubility; plasma protein binding; oxidative cyclisation; thienopyrrole; chloroindole; hepatic glucose output; glucose lowering in vivo;
D O I：
10.1016/j.bmcl.2006.10.037
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A series of substituted 3,4-dihydro-2-quinol one glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site. (c) 2006 Elsevier Ltd. All rights reserved.
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收藏
页码：394 / 399
页数：6
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