PT - JOURNAL ARTICLE AU - Ronald J. Hill AU - Karim Dabbagh AU - Deborah Phippard AU - Ching Li AU - Rebecca T. Suttmann AU - Mary Welch AU - Eva Papp AU - Kyung W. Song AU - Kung-ching Chang AU - David Leaffer AU - Yong-Nam Kim AU - Richard T. Roberts AU - Tanja S. Zabka AU - Dee Aud AU - Joseph Dal Porto AU - Anthony M. Manning AU - Stanford L. Peng AU - David M. Goldstein AU - Brian R. Wong TI - Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity AID - 10.1124/jpet.108.139006 DP - 2008 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 610--619 VI - 327 IP - 3 4099 - http://jpet.aspetjournals.org/content/327/3/610.short 4100 - http://jpet.aspetjournals.org/content/327/3/610.full SO - J Pharmacol Exp Ther2008 Dec 01; 327 AB - P38α is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38α and p38β enzymatic activity, with IC50 values of 0.014 ± 0.002 and 0.48 ± 0.04 μM, respectively. There was no activity against p38δ or p38γ isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH2-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC50, 0.06 μM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) α production by monocytes, interleukin (IL)-1β production in human whole blood, and spontaneous TNFα production by synovial explants from RA patients. LPS- and TNFα-stimulated production of TNFα and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38α with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases. The American Society for Pharmacology and Experimental Therapeutics