Isomeric acetoxy analogues of rofecoxib: A novel class of highly potent and selective cyclooxygenase-2 inhibitors

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 11/2002; 12(19):2753-6. DOI: 10.1016/S0960-894X(02)00537-1
Source: PubMed


A group of isomers possessing a 2-, 3-, or 4-acetoxy moiety on the 3-phenyl substituent of rofecoxib were synthesized that exhibit highly potent, and selective, COX-2 inhibitory activity that have the potential to acetylate the COX-2 isozyme.

Download full-text


Available from: Edward E Knaus, Jan 20, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: 3,4-Dichloro-2(5H)-furanone, which has been prepared efficiently from mucochloric acid, has been transformed selectively into 4-aryl-3-chloro-2(5H)-furanones either by Suzuki- or Stille-type reactions. These monochloro derivatives have been used as precursors either to (Z)-4-aryl-5-[1-(aryl)methylidene]-3-chloro-2(5H)-furanones, including naturally occurring rubrolide M, or to unsymmetrical 3,4-diaryl-2(5H)-furanones. Some 2(5H)-furanone derivatives so prepared have been found to exhibit significant cytotoxic activity in vitro against the NCI three-cell-line panel, but limited cytotoxicity against the NCI human tumor 60 cell-line panel. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
    European Journal of Organic Chemistry 06/2003; 2003(12):2290 - 2302. DOI:10.1002/ejoc.200300097 · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A group of rofecoxib analogs, having a sulfonylazide (SO2N3) substituent in place of the methanesulfonyl (SO2CH3) pharmacophore at the meta-position viz 3-(4-methyl, 4-methoxy, or 4-ethoxyphenyl)-4-(3-sulfonylazidophenyl)-2(5H)furanone (7a-c) and para-position viz 3-phenyl-4-(4-sulfonylazidophenyl)-2(5H)furanone (7d), 3-(4-fluoro, or 4-chlorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e-f) of the C–4 phenyl ring, and 4-(1-oxido-4-pyridyl)-3-phenyl-2(5H)furanone (12) were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies showed that 3-phenyl-4-(4-sulfonylazidophenyl)-2(5H)furanone (7d) inhibited COX-1 selectively (COX-1 IC50 = 0.6659 μM; COX-2 IC50 > 100 μM) and 3-(4-fluorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e) inhibited both enzymes (COX-1 IC50 = 0.8494 μM; COX-2 IC50 = 1.7661 μM). A molecular modeling study was performed where 3-(4-fluorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e) was docked in the active site of murine COX-2 isozyme, which showed that the sulfonylazido group inserts deep into the 2°-pocket of COX-2 where it undergoes both H-bonding (Gln192, Phe518) and weak electrostatic (Arg513) interactions.
    Journal of Heterocyclic Chemistry 03/2004; 40(5):861 - 868. DOI:10.1002/jhet.5570400518 · 0.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new class of acyclic (Z)-2-alkyl-1,2-diphenyl-1-(4-methanesulfonylphenyl)ethenes (7) was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonylphenyl)oct-1-ene (7d) as a potent COX-2 inhibitor (IC(50) = 0.42 microM) with a high COX-2 selectivity index (SI > 234). In a carrageenan-induced rat paw edema assay, (Z)-7d exhibited excellent antiinflammatory activity (ID(50) = 1.1 mg/kg). The molecular modeling and structure-activity data acquired indicate that (Z)-olefins having cis C-1 4-methanesulfonylphenyl and C-2 unsubstituted phenyl (or 4-acetoxyphenyl) substituents in conjunction with a C-1 phenyl ring and a C-2 alkyl substituent of appropriate length constitute a suitable template for the design of a novel class of acyclic (Z)-2-alkyl-1,1,2-triaryleth-1-ene COX-2 inhibitors.
    Journal of Medicinal Chemistry 11/2004; 47(24):6108-11. DOI:10.1021/jm049523y · 5.45 Impact Factor
Show more