Synthesis of celecoxib analogues possessing a N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

J Med Chem. 2009 Mar 26;52(6):1525-9. doi: 10.1021/jm8015188.

Abstract

A novel class of 1-(4-methanesulfonylphenyl and 4-aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole hybrid cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory anti-inflammatory agents was designed. Replacement of the tolyl ring present in celecoxib by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective COX-2/5-LOX inhibitory activities. 1-(4-Aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole exhibited good anti-inflammatory (AI) activity (ED(50) = 27.7 mg/kg po) that compares favorably with the reference drugs celecoxib (ED(50) = 10.8 mg/kg po) and ibuprofen (ED(50) = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of COX-2/5-LOX inhibitory AI drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Celecoxib
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Drug Evaluation, Preclinical
  • Humans
  • Lipoxygenase Inhibitors* / chemical synthesis*
  • Lipoxygenase Inhibitors* / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Spectrophotometry, Infrared
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*

Substances

  • Cyclooxygenase Inhibitors
  • Lipoxygenase Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Celecoxib