Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its methanesulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies

A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs 12a–b) wherein an O2-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, O2-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the bromomethyl group of 5-(4-bromomethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (9a), and its methanesulfonyl analog (9b), were synthesized. The diazen-1-ium-1,2-diolate compounds 12a–b released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (6.1–8.2% range). In comparison, the percentage NO released was significantly higher (76–77% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs 12a–b were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (10a), and its methanesulfonyl analog (10b), would be released from the parent NONO-coxib 12a or 12b upon in vivo cleavage by non-specific serum esterases. The hydroxymethyl compounds 10a–b were weak inhibitors of the cyclooxygenase-1 (COX-1) and COX-2 isozymes (IC50 = 3.7–10.5 μM range). However, the hydroxymethyl compounds 10a–b and the parent NONO-coxibs 12a–b exhibited good AI activities (ED50 = 76.7–111.6 μmol/kg po range) that were greater than that exhibited by the reference drugs aspirin (ED50 = 710 μmol/kg po) and ibuprofen (ED50 = 327 μmol/kg po), but less than that of celecoxib (ED50 = 30.9 μmol/kg po). These studies indicate hybrid ester AI/NO-donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.

Figure optionsDownload as PowerPoint slide