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

Song Seok Shin, Youngjoo Byun, Kyung Min Lim, Jin Kyu Choi, Ki Wha Lee, Joo Hyun Moh, Jin Kwan Kim, Yeon Su Jeong, Ji Young Kim, Young Hoon Choi, Hyun Ju Koh, Young Ho Park, Young Im Oh, Min Soo Noh, Shin Chung

Research output: Contribution to journalArticlepeer-review

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. If, a representative compound for methyl sulfone derivatives, showed a COX-2 IC50 comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED50 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 ED50 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.

Original languageEnglish (US)
Pages (from-to)792-804
Number of pages13
JournalJournal of Medicinal Chemistry
Volume47
Issue number4
DOIs
StatePublished - Feb 12 2004
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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