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

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• 作者：Shuqun Lin ; Stephen T. Wrobleski ; John Hynes Jr. ; Sidney Pitt ; Rosemary Zhang ; Yi Fan ; Arthur M. Doweyko ; Kevin F. Kish ; John S. Sack ; Mary F. Malley ; Susan E. Kiefer ; John A. Newitt ; Murray McKinnon
• 关键词：p38 ; Kinase ; Pyrimidines ; TNF-α ; IL-1β
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 October 2010
• 年：2010
• 卷：20
• 期：19
• 页码：5864-5868
• 全文大小：770 K

文摘

The design, synthesis, and structure–activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen–sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen–sulfur interaction are discussed.