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

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Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017
Cite this: J. Med. Chem. 2007, 50, 11, 2647–2654
Publication Date (Web):May 5, 2007
https://doi.org/10.1021/jm0611004
Copyright © 2007 American Chemical Society

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    Abstract

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    A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFα 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 vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.

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     To whom correspondence should be addressed. Phone:  636-247-7651 (D.R.A.); 636-247-7672 (M.J.M.). Fax:  636-247-5400 (D.R.A.); 636-247-6953 (M.J.M.). E-mail:  [email protected] (D.R.A.); [email protected] (M.J.M.).

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    Combustion analysis data, kinase selectivity assay protocols, CACO-2 assay protocols, ATP competition experiments, and Km determinations. This material is available free of charge via the Internet at http://pubs.acs.org.

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