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Cyclooxygenase-2 inhibitors. Synthesis and pharmacological activities of 5-methanesulfonamido-1-indanone derivatives.

Abstract
The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
AuthorsC S Li, W C Black, C C Chan, A W Ford-Hutchinson, J Y Gauthier, R Gordon, D Guay, S Kargman, C K Lau, J Mancini
JournalJournal of medicinal chemistry (J Med Chem) Vol. 38 Issue 25 Pg. 4897-905 (Dec 08 1995) ISSN: 0022-2623 [Print] United States
PMID8523403 (Publication Type: Journal Article)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Indans
  • L 745337
  • Indomethacin
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
  • Cyclooxygenase Inhibitors (blood, chemical synthesis, pharmacology)
  • Humans
  • Indans (blood, chemical synthesis, pharmacology)
  • Indomethacin (pharmacology)
  • Magnetic Resonance Spectroscopy
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Saimiri
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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