2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization

被引：16

作者：

Harris, Christopher M. ^{[1
]}

Ericsson, Anna M. ^{[1
]}

Argiriadi, Maria A. ^{[1
]}

Barberis, Claude ^{[1
]}

Borhani, David W. ^{[1
]}

Burchat, Andrew ^{[1
]}

Calderwood, David J. ^{[1
]}

Cunha, George A. ^{[1
]}

Dixon, Richard W. ^{[1
]}

Frank, Kristine E. ^{[1
]}

Johnson, Eric F. ^{[1
]}

Kamens, Joanne ^{[1
]}

Kwak, Silvia ^{[1
]}

Li, Biqin ^{[1
]}

Mullen, Kelly D. ^{[1
]}

Perron, Denise C. ^{[1
]}

Wang, Lu ^{[1
]}

Wishart, Neil ^{[1
]}

Wu, Xiaoyun ^{[1
]}

Zhang, Xiaolei ^{[1
]}

Zmetra, Tami R. ^{[1
]}

Talanian, Robert V. ^{[1
]}

机构：

[1] Abbott Labs, Worcester, MA 01605 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 01期

关键词：

MAPKAP-K2; MK2; TNF alpha; Diaminopyrimidine;

D O I：

10.1016/j.bmcl.2009.10.103

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC50 values as low as 19 nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNF alpha production in peripheral human monocytes. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：334 / 337

页数：4

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