Celecoxib prodrugs possessing a diazen-1-ium-1,2-diolate nitric oxide donor moiety: synthesis, biological evaluation and nitric oxide release studies.

摘要: A new class of anti-inflammatory (AI) cupferron prodrugs was synthesized wherein a diazen-1-ium-1,2-diolato ammonium salt, and its O(2)-methyl O(2)-acetoxyethyl derivatives, nitric oxide (NO) donor moieties were attached directly to an aryl carbon on celecoxib template. The percentage NO released from the compounds higher (18.0-37.8% theoretical maximal release one molecule NO/molecule parent compound) upon incubation in presence rat serum, relative with phosphate buffer saline (PBS) at pH 7.4 (3.8-11.6% range). All exhibited weak inhibition COX-1 isozyme (IC(50)=5.8-17.0 microM range) conjunction or modest COX-2 (IC(50)=1.6-14.4 most potent AI agent 5-[4-(O(2)-ammonium diazen-1-ium-1,2-diolato)phenyl]-1-(4-sulfamoylphenyl)-3-trifluoromethyl-1H-pyrazole potency that about fourfold twofold greater than observed for respective reference drugs aspirin ibuprofen. These studies indicate use template constitutes plausible drug design approach targeted toward development do not cause gastric irritation, elevate blood pressure induce platelet aggregation have been associated some selective inhibitors.