In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives

J Med Chem. 2004 Feb 12;47(4):792-804. doi: 10.1021/jm020545z.

Abstract

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Arthritis, Experimental / drug therapy
  • Carrageenan
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacology
  • Cyclooxygenase Inhibitors / toxicity
  • Edema / chemically induced
  • Edema / drug therapy
  • Furans / chemical synthesis*
  • Furans / pharmacology
  • Furans / toxicity
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / blood
  • Isoenzymes / metabolism
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / enzymology
  • Male
  • Membrane Proteins
  • Mice
  • Models, Molecular
  • Prostaglandin-Endoperoxide Synthases / blood
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stomach Ulcer / chemically induced
  • Structure-Activity Relationship

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Furans
  • Isoenzymes
  • Membrane Proteins
  • Carrageenan
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Ptgs1 protein, rat