SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): Discovery of antagonist SB-568849

被引：30

作者：

Witty, David R. ^{[1
]}

Bateson, John H. ^{[1
]}

Hervieu, Guillaume J. ^{[1
]}

Jeffrey, Phillip ^{[1
]}

Johnson, Christopher N. ^{[1
]}

Muir, Alison I. ^{[1
]}

O'Hanlon, Peter J. ^{[1
]}

Stemp, Geoffrey ^{[1
]}

Stevens, Alex J. ^{[1
]}

Thewlis, Kevin M. ^{[1
]}

Wilson, Shelagh ^{[1
]}

Winborn, Kim Y. ^{[1
]}

机构：

[1] GlaxoSmithKline, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 18期

关键词：

MCH; MCH R1; biphenylearboxamide; antagonist; melanin-concentrating hormone; obesity; feeding; stress; anxiety;

D O I：

10.1016/j.bmcl.2006.06.056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability. (c) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：4865 / 4871

页数：7

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