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.
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.
Chowdhury
Morshed Alam
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G2N8.
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Knaus
Edward E
EE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002351:Carrageenan; D000068579:Celecoxib; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D002351:Carrageenan; D000068579:Celecoxib; D001241:Aspirin