Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: Preclinical-to-clinical translation

Heidi R. Hope, Gary D. Anderson, Barry L. Burnette, Robert P. Compton, Rajesh V. Devraj, Jeffrey L. Hirsch, Robert H. Keith, Xiong Li, Gabriel Mbalaviele, Dean M. Messing, Matthew J. Saabye, John F. Schindler, Shaun R. Selness, Loreen I. Stillwell, Elizabeth G. Webb, Jian Zhang, Joseph B. Monahan

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 K i = 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.

Original languageEnglish
Pages (from-to)882-895
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number3
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

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    Hope, H. R., Anderson, G. D., Burnette, B. L., Compton, R. P., Devraj, R. V., Hirsch, J. L., Keith, R. H., Li, X., Mbalaviele, G., Messing, D. M., Saabye, M. J., Schindler, J. F., Selness, S. R., Stillwell, L. I., Webb, E. G., Zhang, J., & Monahan, J. B. (2009). Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: Preclinical-to-clinical translation. Journal of Pharmacology and Experimental Therapeutics, 331(3), 882-895. https://doi.org/10.1124/jpet.109.158329