PT - JOURNAL ARTICLE AU - Heidi R. Hope AU - Gary D. Anderson AU - Barry L. Burnette AU - Robert P. Compton AU - Rajesh V. Devraj AU - Jeffrey L. Hirsch AU - Robert H. Keith AU - Xiong Li AU - Gabriel Mbalaviele AU - Dean M. Messing AU - Matthew J. Saabye AU - John F. Schindler AU - Shaun R. Selness AU - Loreen I. Stillwell AU - Elizabeth G. Webb AU - Jian Zhang AU - Joseph B. Monahan TI - Anti-Inflammatory Properties of a Novel <em>N</em>-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation AID - 10.1124/jpet.109.158329 DP - 2009 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 882--895 VI - 331 IP - 3 4099 - http://jpet.aspetjournals.org/content/331/3/882.short 4100 - http://jpet.aspetjournals.org/content/331/3/882.full SO - J Pharmacol Exp Ther2009 Dec 01; 331 AB - Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the N-phenyl pyridinone p38 MAP kinase inhibitor benzamide [3- [3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (−)-(9CI); PH-797804]. PH-797804 is an ATP-competitive, readily reversible inhibitor of the α isoform of human p38 MAP kinase, exhibiting a Ki = 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E2, at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-α and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and anti-inflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.© 2009 by The American Society for Pharmacology and Experimental Therapeutics