RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase

Scott A. Wadsworth, Druie E. Cavender, Scott A. Beers, Praful Lalan, Peter H. Schafer, Elizabeth A. Malloy, Wei Wu, Bohumila Fahmy, Gilbert C. Olini, Janet E. Davis, J. Lee Pellegrino-Gensey, Michael P. Wachter, John J. Siekierka

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164 Scopus citations


Tumor necrosis factor-α (TNF-α), a cytokine secreted by activated monocytes/macrophages and T lymphocytes, has been implicated in several disease states, including rheumatoid arthritis, inflammatory bowel disease, septic shock, and osteoporosis. Monocyte/macrophage production of TNF-α is dependent on the mitogen-activated protein kinase p38. RWJ 67657 (4-[4-(4- fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1- ol) inhibited the release of TNF-α by lipopolysaccharide (a monocyte stimulus)-treated human peripheral blood mononuclear cells with an IC50 of 3 nM, as well as the release of TNF-α from peripheral blood mononuclear cells treated with the superantigen staphylococcal enterotoxin B (a T cell stimulus), with an IC50 value of 13 nM. This compound was approximately 10- fold more potent than the literature standard p38 kinase inhibitor SB 203580 in all p38 dependent in vitro systems tested. RWJ 67657 inhibited the enzymatic activity of recombinant p38α and β, but not γ, or δ, in vitro and had no significant activity against a variety of other enzymes. In contrast, SB 203580 significantly inhibited the tyrosine kinases p56 lck and c-src (IC50 = 5 μM). RWJ 67657 did not inhibit T cell production of interleukin-2 or interferon-γ, and did not inhibit T cell proliferation in response to mitogens. RWJ 67657 inhibited TNF-α production in lipopolysaccharide-injected mice (87% inhibition at 50 mg/kg) and in rats (91% inhibition at 25 mg/kg) after oral administration. Based on these favorable biological properties, RWJ 67657 may have use as a treatment for inflammatory diseases.

Original languageEnglish
Pages (from-to)680-687
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Nov 1999


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