Novel (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic ester prodrugs possessing a diazen-1-ium-1,2-diolate moiety: Design, synthesis, cyclooxygenase inhibition, and nitric oxide release studies

A novel group of hybrid nitric oxide-releasing anti-inflammatory drugs (11) possessing a 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, or 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, nitric oxide (·NO) donor moiety attached via a one-carbon methylene spacer to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. These ester prodrugs (11) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC50 = 0.94–31.6 μM range). All compounds released ·NO upon incubation with phosphate buffer (PBS) at pH 7.4 (3.2–11.3% range). In comparison, the percentage of ·NO released was significantly higher (48.6–75.3% range) when these hybrid ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both ·NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases. O2-[(E)-2-(4-Acetylaminophenyl)-3-(4-methanesulfonylphenyl)acryloyloxymethyl]-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11f) is a moderately potent (IC50 = 0.94 μM) and selective (SI > 104) COX-2 inhibitor that released 73% of the theoretical maximal release of two molecules of ·NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester ·NO-donor prodrugs offer a potential drug design concept for the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular side effects.

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