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.

引用

页码：394 / 399

页数：6

共 16 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].