The discovery of benzanilides as c-Met receptor tyrosine kinase inhibitors by a directed screening approach

被引：12

作者：

Allen, Joanne V. ^{[1
]}

Bardelle, Catherine ^{[1
]}

Blades, Kevin ^{[1
]}

Buttar, Dave ^{[1
]}

Chapman, Louise ^{[1
]}

Colclough, Nicola ^{[1
]}

Dossetter, Alexander G. ^{[1
]}

Garner, Andrew P. ^{[1
]}

Girdwood, Alan ^{[1
]}

Lambert, Christine ^{[1
]}

Leach, Andrew G. ^{[1
]}

Law, Brian ^{[1
]}

Major, John ^{[1
]}

Plant, Helen ^{[1
]}

Slater, Anthony M. ^{[1
]}

机构：

[1] AstraZeneca R&D, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 18期

关键词：

c-Met; Kinase; Directed screening; Ligand efficiency; Secondary metabolism; Bio-isosteres; Decisions; Benzanilides; SMALL-MOLECULE INHIBITOR; IN-VIVO; GROWTH; 3-CARBOXY-BETA-CARBOLINES; PROTOONCOGENE; OPTIMIZATION; DERIVATIVES; ACTIVATION; POTENT; GAB1;

D O I：

10.1016/j.bmcl.2011.07.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：5224 / 5229

页数：6

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