PMID- 10525088
OWN - NLM
STAT- MEDLINE
DCOM- 19991124
LR  - 20161124
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 291
IP  - 2
DP  - 1999 Nov
TI  - RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein 
      kinase.
PG  - 680-7
AB  - 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.
FAU - Wadsworth, S A
AU  - Wadsworth SA
AD  - Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Raritan, New 
      Jersey 08869, USA.
FAU - Cavender, D E
AU  - Cavender DE
FAU - Beers, S A
AU  - Beers SA
FAU - Lalan, P
AU  - Lalan P
FAU - Schafer, P H
AU  - Schafer PH
FAU - Malloy, E A
AU  - Malloy EA
FAU - Wu, W
AU  - Wu W
FAU - Fahmy, B
AU  - Fahmy B
FAU - Olini, G C
AU  - Olini GC
FAU - Davis, J E
AU  - Davis JE
FAU - Pellegrino-Gensey, J L
AU  - Pellegrino-Gensey JL
FAU - Wachter, M P
AU  - Wachter MP
FAU - Siekierka, J J
AU  - Siekierka JJ
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antigens)
RN  - 0 (Enterotoxins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Interleukin-2)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Pyridines)
RN  - 0 (RWJ 67657)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Animals
MH  - Antigens/immunology
MH  - Cell Division/drug effects
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Enterotoxins/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - In Vitro Techniques
MH  - Interferon-gamma/metabolism
MH  - Interleukin-2/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - Monocytes/*metabolism
MH  - Protein Kinases/*metabolism
MH  - Pyridines/*pharmacology
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Staphylococcus/physiology
MH  - T-Lymphocytes/drug effects/metabolism
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
EDAT- 1999/10/19 00:00
MHDA- 1999/10/19 00:01
CRDT- 1999/10/19 00:00
PHST- 1999/10/19 00:00 [pubmed]
PHST- 1999/10/19 00:01 [medline]
PHST- 1999/10/19 00:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 1999 Nov;291(2):680-7.