The development of novel inhibitors of tumor necrosis factor-alpha (TNF-alpha) production based on substituted [5,5]-bicyclic pyrazolones

Bioorg Med Chem Lett. 2004 Aug 16;14(16):4267-72. doi: 10.1016/j.bmcl.2004.06.001.


Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Lipopolysaccharides / pharmacology
  • Models, Molecular
  • Pyrazolones / administration & dosage
  • Pyrazolones / chemistry*
  • Pyrazolones / pharmacokinetics
  • Pyrazolones / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Lipopolysaccharides
  • Pyrazolones
  • Tumor Necrosis Factor-alpha