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.
W C Black  1 ,  C Brideau ,  C C Chan ,  S Charleson ,  N Chauret ,  D Claveau ,  D Ethier ,  R Gordon ,  G Greig ,  J Guay ,  G Hughes ,  P Jolicoeur ,  Y Leblanc ,  D Nicoll-Griffith ,  N Ouimet ,  D Riendeau ,  D Visco ,  Z Wang ,  L Xu ,  P Prasit
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8, and Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
PMID: 10197970 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.