Article

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

ABSTRACT

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

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)
    No preview · Article · Jun 2003 · European Journal of Organic Chemistry
  • [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.
    No preview · Article · Mar 2004 · Journal of Heterocyclic Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO(2) pharmacophore at the para-position of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.02 microM; COX-1 IC(50) > 100 microM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC(50) = 0.07 microM; SI = 474) and rofecoxib (COX-2 IC(50) = 0.50 microM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID(50) = 5.6 mg/kg) than celecoxib (ID(50) = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.45 microM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO(2)Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO(2)Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO(2)Me pharmacophore within the COX-2 secondary pocket.
    No preview · Article · Aug 2004 · Journal of Medicinal Chemistry
Show more