![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 291, Issue 2, 680-687, November 1999
Drug Discovery, The R. W. Johnson Pharmaceutical Research
Institute, Raritan, New Jersey
Tumor necrosis factor-
(TNF-), 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- 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- by lipopolysaccharide (a
monocyte stimulus)-treated human peripheral blood mononuclear cells
with an IC50 of 3 nM, as well as the release of TNF-
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 p38 and 
, but not
or 
, 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- and did not inhibit T
cell proliferation in response to mitogens. RWJ 67657 inhibited TNF-
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.
This article has been cited by other articles:
|
|
 |
|
  K. Muthumani, A. Y. Choo, D. J. Shedlock, D. J. Laddy, S. G. Sundaram, L. Hirao, L. Wu, K. P. Thieu, C. W. Chung, K. M. Lankaraman, et al. Human Immunodeficiency Virus Type 1 Nef Induces Programmed Death 1 Expression through a p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Virol., December 1, 2008; 82(23): 11536 - 11544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Schett, J Zwerina, and G Firestein The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis Ann Rheum Dis, July 1, 2008; 67(7): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Kompa, F. See, D. A. Lewis, A. Adrahtas, D. M. Cantwell, B. H. Wang, and H. Krum Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, C. S. K. Kam, F. Q. Liu, Y. Liu, V. C. H. Lui, J. R. Lamb, and P. K. H. Tam LPS-induced up-regulation of TGF-{beta} receptor 1 is associated with TNF-{alpha} expression in human monocyte-derived macrophages J. Leukoc. Biol., May 1, 2008; 83(5): 1165 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wei, B. J. Daniel, M. J. Brumlik, M. E. Burow, W. Zou, I. A. Khan, S. Wadsworth, J. Siekierka, and T. J. Curiel Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection Antimicrob. Agents Chemother., December 1, 2007; 51(12): 4324 - 4328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sato, T. Horinouchi, D. S. Hutchinson, B. A. Evans, and R. J. Summers Ligand-Directed Signaling at the beta3-Adrenoceptor Produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) Relative to Receptor Agonists Mol. Pharmacol., November 1, 2007; 72(5): 1359 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kammerer, H. Scheible, W. Albrecht, C. H. Gleiter, and S. Laufer Pharmacokinetics of ML3403 ({4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine), a 4-Pyridinylimidazole-Type p38 Mitogen-Activated Protein Kinase Inhibitor Drug Metab. Dispos., June 1, 2007; 35(6): 875 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Westra, J Bijzet, B Doornbos-van der Meer, M H van Rijswijk, and P C Limburg Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute phase protein synthesis in human hepatoma cell lines Ann Rheum Dis, July 1, 2006; 65(7): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Frigo, A. Basu, E. N. Nierth-Simpson, C. B. Weldon, C. M. Dugan, S. Elliott, B. M. Collins-Burow, V. A. Salvo, Y. Zhu, L. I. Melnik, et al. p38 Mitogen-Activated Protein Kinase Stimulates Estrogen-Mediated Transcription and Proliferation through the Phosphorylation and Potentiation of the p160 Coactivator Glucocorticoid Receptor-Interacting Protein 1 Mol. Endocrinol., May 1, 2006; 20(5): 971 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Conway, B. McDonald, J. Parham, B. Keith, D. W. Rusnak, E. Shaw, M. Jansen, P. Lin, A. Payne, R. M. Crosby, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580 PNAS, November 1, 2005; 102(44): 16078 - 16083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Muthumani, A. Y. Choo, D. S. Hwang, A. Premkumar, N. S. Dayes, C. Harris, D. R. Green, S. A. Wadsworth, J. J. Siekierka, and D. B. Weiner HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation Blood, September 15, 2005; 106(6): 2059 - 2068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Zijlstra, J. E. Tulleken, J. J.M. Ligtenberg, P. de Boer, and T. S. van der Werf p38-MAPK inhibition and endotoxin induced tubular dysfunction in men Innate Immunity, December 1, 2004; 10(6): 402 - 405. [Abstract] [PDF]
|
|
|
|
|
|
J Westra, P C Limburg, P de Boer, and M H van Rijswijk Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts Ann Rheum Dis, November 1, 2004; 63(11): 1453 - 1459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. See, W. Thomas, K. Way, A. Tzanidis, A. Kompa, D. Lewis, S. Itescu, and H. Krum p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat J. Am. Coll. Cardiol., October 19, 2004; 44(8): 1679 - 1689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Parasrampuria, P. de Boer, D. Desai-Krieger, A. T. Chow, and C. R. Jones Single-Dose Pharmacokinetics and Pharmacodynamics of RWJ 67657, a Specific p38 Mitogen-Activated Protein Kinase Inhibitor: A First-in-Human Study J. Clin. Pharmacol., April 1, 2003; 43(4): 406 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cabane, W. Englaro, K. Yeow, M. Ragno, and B. Derijard Regulation of C2C12 myogenic terminal differentiation by MKK3/p38alpha pathway Am J Physiol Cell Physiol, March 1, 2003; 284(3): C658 - C666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Huang, Y. Wang, M. Collins, J. J. Gu, B. S. Mitchell, and L. M. Graves Inhibition of Nucleoside Transport by p38 MAPK Inhibitors J. Biol. Chem., August 2, 2002; 277(32): 28364 - 28367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Carballo, H. Cao, W. S. Lai, E. A. Kennington, D. Campbell, and P. J. Blackshear Decreased Sensitivity of Tristetraprolin-deficient Cells to p38 Inhibitors Suggests the Involvement of Tristetraprolin in the p38 Signaling Pathway J. Biol. Chem., November 2, 2001; 276(45): 42580 - 42587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
|
|
|
|
|
|
D. A. Linseman, T. Laessig, M. K. Meintzer, M. McClure, H. Barth, K. Aktories, and K. A. Heidenreich An Essential Role for Rac/Cdc42 GTPases in Cerebellar Granule Neuron Survival J. Biol. Chem., October 12, 2001; 276(42): 39123 - 39131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takahashi, Y. Keto, T. Fujita, T. Uchiyama, and A. Yamamoto FR167653, a p38 Mitogen-Activated Protein Kinase Inhibitor, Prevents Helicobacter pylori-Induced Gastritis in Mongolian Gerbils J. Pharmacol. Exp. Ther., January 1, 2001; 296(1): 48 - 56. [Abstract] [Full Text]
|
|
|
|
|
|
M. Feldmann, J. Miotla, E. Paleolog, R. Williams, A.-M. Malfait, P. Taylor, F. M Brennan, and R. N Maini Future prospects for anti-cytokine treatment Ann Rheum Dis, November 1, 2000; 59(90001): i119 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lafont, J. Liautard, M. Sable-Teychene, Y. Sainte-Marie, and J. Favero Isopentenyl Pyrophosphate, a Mycobacterial Non-peptidic Antigen, Triggers Delayed and Highly Sustained Signaling in Human gamma delta T Lymphocytes without Inducing Down-modulation of T Cell Antigen Receptor J. Biol. Chem., May 4, 2001; 276(19): 15961 - 15967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lafont, J. Liautard, A. Gross, J. P. Liautard, and J. Favero Tumor Necrosis Factor-alpha Production Is Differently Regulated in gamma delta and alpha beta Human T Lymphocytes J. Biol. Chem., June 16, 2000; 275(25): 19282 - 19287. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
