Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

被引：39

作者：

McCoull, William ^{[1
]}

Addie, Matthew S. ^{[1
]}

Birch, Alan M. ^{[1
]}

Birtles, Susan ^{[1
]}

Buckett, Linda K. ^{[1
]}

Butlin, Roger J. ^{[1
]}

Bowker, Suzanne S. ^{[1
]}

Boyd, Scott ^{[1
]}

Chapman, Stephen ^{[1
]}

Davies, Robert D. M. ^{[1
]}

Donald, Craig S. ^{[1
]}

Green, Clive P. ^{[1
]}

Jenner, Chloe ^{[1
]}

Kemmitt, Paul D. ^{[1
]}

Leach, Andrew G. ^{[1
]}

Moody, Graeme C. ^{[1
]}

Gutierrez, Pablo Morentin ^{[1
]}

Newcombe, Nicholas J. ^{[1
]}

Nowak, Thorsten ^{[1
]}

Packer, Martin J. ^{[1
]}

Plowright, Alleyn T. ^{[1
]}

Revill, John ^{[1
]}

Schofield, Paul ^{[1
]}

Sheldon, Chris ^{[1
]}

Stokes, Steve ^{[1
]}

Turnbull, Andrew V. ^{[1
]}

Wang, Steven J. Y. ^{[1
]}

Whalley, David P. ^{[1
]}

Wood, J. Matthew ^{[1
]}

机构：

[1] AstraZeneca, Cardiovasc & Gastrointestinal Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 12期

关键词：

DGAT; Oxadiazole; LLE; Obesity; PK/PD; DIACYLGLYCEROL ACYLTRANSFERASE-1 INHIBITORS; POTENT; DISCOVERY; DERIVATIVES; DESIGN;

D O I：

10.1016/j.bmcl.2012.04.117

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3873 / 3878

页数：6

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