TY - JOUR T1 - A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 797 LP - 807 DO - 10.1124/jpet.110.166173 VL - 333 IS - 3 AU - Robert J. Mourey AU - Barry L. Burnette AU - Sarah J. Brustkern AU - J. Scott Daniels AU - Jeffrey L. Hirsch AU - William F. Hood AU - Marvin J. Meyers AU - Stephen J. Mnich AU - Betsy S. Pierce AU - Matthew J. Saabye AU - John F. Schindler AU - Sarah A. South AU - Elizabeth G. Webb AU - Jian Zhang AU - David R. Anderson Y1 - 2010/06/01 UR - http://jpet.aspetjournals.org/content/333/3/797.abstract N2 - Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (Ki = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFα production with similar activity (IC50 = 160 nM). PF-3644022 blocks TNFα and IL-6 production in LPS-stimulated human whole blood with IC50 values of 1.6 and 10.3 μM, respectively. Inhibition of TNFα in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFα model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFα production in the acute model and inhibition of paw swelling in the chronic model is observed with ED50 values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a Cmin higher than the EC50 measured in the rat LPS-induced TNFα model. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -