2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors

J Med Chem. 1999 Apr 8;42(7):1274-81. doi: 10.1021/jm980642l.

Abstract

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.

MeSH terms

  • Analgesics, Non-Narcotic / chemical synthesis
  • Analgesics, Non-Narcotic / chemistry
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Non-Narcotic / toxicity
  • Animals
  • Arthritis, Experimental / drug therapy
  • Biological Availability
  • CHO Cells
  • Carrageenan / toxicity
  • Cell Line
  • Cricetinae
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Cyclooxygenase Inhibitors / toxicity
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology
  • Cyclopentanes / toxicity
  • Digestive System / drug effects
  • Edema / chemically induced
  • Edema / drug therapy
  • Female
  • Fever / drug therapy
  • Humans
  • Hyperalgesia / drug therapy
  • Isoenzymes / metabolism*
  • Male
  • Membrane Proteins
  • Microsomes / enzymology
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Sulfones / toxicity
  • Transfection

Substances

  • Analgesics, Non-Narcotic
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Cyclopentanes
  • Isoenzymes
  • L 776967
  • L 784506
  • Membrane Proteins
  • Sulfones
  • Carrageenan
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, rat