Synthesis of new 4-[2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines: a search for novel nitric oxide donor anti-inflammatory agents |
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Authors: | Chowdhury Morshed Alam Abdellatif Khaled R A Dong Ying Knaus Edward E |
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Institution: | Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G2N8. |
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Abstract: | A group of 4-2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines possessing a variety of substituents (Me, CO2Et, H, N=O) attached to the 1,2,3,6-tetrahydropyridyl N(1)-nitrogen atom were synthesized and evaluated as anti-inflammatory agents. Structure-activity relationship data showed that the N-methyl-1,2,3,6-tetrahydropyridyl moiety is a suitable bioisosteric replacement for the tolyl moiety in celecoxib. The most potent compound 4-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonamide (ED(50)=61.2 mg/kg po) exhibited an anti-inflammatory activity between that of the reference drugs celecoxib (ED(50)=10.8 mg/kg po) and aspirin (ED(50)=128.7 mg/kg po). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 4-2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines requires further investigation since the reaction of 1,2,3,6-tetrahydropyridines with nitric oxide furnished the undesired N-nitroso-1,2,3,6-tetrahydrohydropyridyl product rather than the desired N-diazen-1-ium-1,2-diolate-1,2,3,6-tetrahydropyridyl product. |
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