RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase.
Tumor necrosis factor-alpha (TNF-alpha), 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-alpha 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-alpha by lipopolysaccharide (a monocyte stimulus)-treated human peripheral blood mononuclear cells with an IC(50) of 3 nM, as well as the release of TNF-alpha from peripheral blood mononuclear cells treated with the superantigen staphylococcal enterotoxin B (a T cell stimulus), with an IC(50) 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 p38alpha and beta, but not gamma or delta, 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 (IC(50) = 5 microM). RWJ 67657 did not inhibit T cell production of interleukin-2 or interferon-gamma and did not inhibit T cell proliferation in response to mitogens. RWJ 67657 inhibited TNF-alpha 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.
Wadsworth
S A
SA
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869, USA.
Cavender
D E
DE
Beers
S A
SA
Lalan
P
P
Schafer
P H
PH
Malloy
E A
EA
Wu
W
W
Fahmy
B
B
Olini
G C
GC
Davis
J E
JE
Pellegrino-Gensey
J L
JL
Wachter
M P
MP
Siekierka
J J
JJ
D000818:Animals; D000941:Antigens / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013210:Staphylococcus / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000941:Antigens; D004768:Enterotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D008070:Lipopolysaccharides; D011725:Pyridines; C400277:RWJ 67657; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011494:Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580