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Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis.

Abstract
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
AuthorsLaszlo Revesz, Ernst Blum, Franco E Di Padova, Thomas Buhl, Roland Feifel, Hermann Gram, Peter Hiestand, Ute Manning, Gerard Rucklin
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 13 Pg. 3595-9 (Jul 05 2004) ISSN: 0960-894X [Print] England
PMID15177482 (Publication Type: Journal Article)
Chemical References
  • Antirheumatic Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • Oxazoles
  • Pyridines
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Collagen
  • p38 Mitogen-Activated Protein Kinases
Topics
  • Animals
  • Antirheumatic Agents (chemical synthesis, pharmacology, therapeutic use)
  • Arthritis, Experimental (chemically induced, drug therapy)
  • Collagen
  • Disease Models, Animal
  • Enzyme Inhibitors (chemical synthesis, pharmacology)
  • Imidazoles (chemistry)
  • Lipopolysaccharides (pharmacology)
  • Mice
  • Oxazoles (chemistry)
  • Pyridines (chemical synthesis, pharmacology, therapeutic use)
  • Rats
  • Structure-Activity Relationship
  • Thiazoles (chemistry)
  • Tumor Necrosis Factor-alpha (metabolism)
  • p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)

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