Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile

Bioorg Med Chem Lett. 2002 Nov 18;12(22):3317-20. doi: 10.1016/s0960-894x(02)00739-4.

Abstract

The COX-2 inhibitor DFP [5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone] was found to have a long half-life in humans. Analogues have been characterized in order to optimize pharmacokinetics. This has lead to the discovery of 5(S)-(5-ethyl-5-methyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone analogue 11 a potent and selective COX-2 inhibitor which is metabolized to a greater extent than DFP upon incubation with rat and human hepatocytes, suggesting a shorter half-life in humans.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Hepatocytes / metabolism
  • Humans
  • Indomethacin / pharmacology
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors*
  • Lactones / chemical synthesis
  • Lactones / metabolism
  • Lactones / pharmacology*
  • Membrane Proteins
  • Pharmacokinetics*
  • Prostaglandin-Endoperoxide Synthases
  • Rats
  • Structure-Activity Relationship
  • Sulfones

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Lactones
  • Membrane Proteins
  • Sulfones
  • rofecoxib
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Indomethacin