RT Journal Article
SR Electronic
T1 RWJ 67657, a Potent, Orally Active Inhibitor of p38 Mitogen-Activated Protein Kinase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 680
OP 687
VO 291
IS 2
A1 Scott A. Wadsworth
A1 Druie E. Cavender
A1 Scott A. Beers
A1 Praful Lalan
A1 Peter H. Schafer
A1 Elizabeth A. Malloy
A1 Wei Wu
A1 Bohumila Fahmy
A1 Gilbert C. Olini
A1 Janet E. Davis
A1 J. Lee Pellegrino-Gensey
A1 Michael P. Wachter
A1 John J. Siekierka
YR 1999
UL http://jpet.aspetjournals.org/content/291/2/680.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics