Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: reversal cyclooxygenase-2 selectivity by sulfonamide group removal

J Med Chem. 2004 Sep 23;47(20):4881-90. doi: 10.1021/jm040782x.

Abstract

3,4-Diarylisoxazole analogues of valdecoxib [4-(5-methyl-3-phenylisoxazol-4-yl)-benzensulfonamide], a selective cyclooxygenase-2 (COX-2) inhibitor, were synthesized by 1,3-dipolar cycloaddition of arylnitrile oxides to the enolate ion of phenylacetone regioselectively prepared in situ with lithium diisopropylamide at 0 degrees C. The corresponding 3-aryl-5-methyl-4-phenylisoxazoles were easily generated by a dehydration/aromatization reaction under basic conditions of 3-aryl-5-hydroxy-5-methyl-4-phenyl-2-isoxazolines and further transformed into their benzenesulfonamide derivatives. The biochemical COX-1/COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isozyme activity. Three compounds not bearing the sulfonamide group present in valdecoxib were selective COX-1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biochemistry / methods
  • Blood / drug effects
  • Blood / metabolism
  • Blood Platelets / drug effects
  • Blood Platelets / enzymology
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dinoprostone / metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Lipopolysaccharides / pharmacology
  • Membrane Proteins
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology
  • Thromboxane B2 / metabolism

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Isoxazoles
  • Lipopolysaccharides
  • Membrane Proteins
  • Sulfonamides
  • valdecoxib
  • Thromboxane B2
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone