Pyrrolopyridine Inhibitors of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK-2)

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• 作者：David R. Anderson ; Marvin J. Meyers ; William F. Vernier ; Matthew W. Mahoney ; Ravi G. Kurumbail ; Nicole Caspers ; Gennadiy I. Poda ; John F. Schindler ; David B. Reitz ; Robert J. Mourey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 31, 2007
• 年：2007
• 卷：50
• 期：11
• 页码：2647 - 2654
• 全文大小：352K
• 年卷期：v.50,no.11(May 31, 2007)
• ISSN：1520-4804

文摘

A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. Theseinhibitors have IC₅₀ values as low as 10 nM against the target and have good selectivity profiles against anumber of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppressTNFges/gifchars/alpha.gif" BORDER=0> production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivomodels are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.