Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

被引：31

作者：

Lin, Shuqun ^{[1
]}

Wrobleski, Stephen T. ^{[1
]}

Hynes, John, Jr. ^{[1
]}

Pitt, Sidney ^{[2
]}

Zhang, Rosemary ^{[2
]}

Fan, Yi ^{[2
]}

Doweyko, Arthur M. ^{[3
]}

Kish, Kevin F. ^{[3
]}

Sack, John S. ^{[3
]}

Malley, Mary F. ^{[3
]}

Kiefer, Susan E. ^{[3
]}

Newitt, John A. ^{[3
]}

McKinnon, Murray ^{[2
]}

Trzaskos, James ^{[2
]}

Barrish, Joel C. ^{[1
]}

Dodd, John H. ^{[1
]}

Schieven, Gary L. ^{[2
]}

Leftheris, Katerina ^{[1
]}

机构：

[1] Bristol Myers Squibb Pharmaceut Res Inst, Dept Chem Immunol, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Pharmaceut Res Inst, Dept Immunol Biol, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Pharmaceut Res Inst, Dept Mol Biosci, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 19期

关键词：

p38; Kinase; Pyrimidines; TNF-alpha; IL-1; beta; P38; CHEMOTYPES; DISCOVERY; POTENT;

D O I：

10.1016/j.bmcl.2010.07.102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38 alpha MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38 alpha inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38 alpha active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 alpha and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5864 / 5868

页数：5

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