Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

被引：53

作者：

Xu, Guozhang ^{[1
]}

Searle, Lily Lee ^{[1
]}

Hughes, Terry V. ^{[1
]}

Beck, Amanda K. ^{[1
]}

Connolly, Peter J. ^{[1
]}

Abad, Marta C. ^{[1
]}

Neeper, Michael P. ^{[1
]}

Struble, Geoffrey T. ^{[1
]}

Springer, Barry A. ^{[1
]}

Emanuel, Stuart L. ^{[1
]}

Gruninger, Robert H. ^{[1
]}

Pandey, Niranjan ^{[1
]}

Adams, Mary ^{[1
]}

Moreno-Mazza, Sandra ^{[1
]}

Fuentes-Pesquera, Angel R. ^{[1
]}

Middleton, Steven A. ^{[1
]}

Greenberger, Lee M. ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev, Cranbury, NJ 08512 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 12期

关键词：

receptor tyrosine kinase; ErbB-2; EGFR; oxime; quinazoline; bioisostere;

D O I：

10.1016/j.bmcl.2008.05.024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC50 values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3495 / 3499

页数：5

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