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J Med Chem. 2003 Nov 6;46(23):4872-82.

Design, synthesis, and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors.

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  • 1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada.


A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.

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