Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety
A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs), in which an O2 ‑acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-aminosulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids (6a–...
| Autores: | , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2018 |
| País: | Brasil |
| Recursos: | Universidade de São Paulo (USP) |
| Repositório: | Brazilian Journal of Pharmaceutical Sciences |
| Idioma: | inglês |
| OAI Identifier: | oai:revistas.usp.br:article/159275 |
| Acesso em linha: | https://www.revistas.usp.br/bjps/article/view/159275 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Anti-inflammatory/development/drugs NONO-coxib esters 1,5-dihydropyrazoles |
| Resumo: | A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs), in which an O2 ‑acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-aminosulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids (6a–c), were synthesized. A low amount of NO was released from the diazen-1-ium-1,2-diolate compounds 6a–c upon incubation with phosphate buffer saline (PBS) at pH 7.4 (range: pH 7.97–8.51), whereas, the percentage of NO released was significantly higher (84.5%–85.05% 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 were incubated in the presence of rat serum. These incubation studies demonstrated that both NO and the anti-inflammatory 1-(4-aminosulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H‑pyrazol-3-carboxylic acid (4a–c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The parent compounds 4a-c displayed good antiinflammatory effects (ID50=81.4–112.4 mg/kg p.o.) between those exhibited by the reference drugs, aspirin (ID50=114.3 mg/kg p.o.) and celecoxib (ID50=12.6 mg/kg p.o.). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO‑coxibs) offer a potential drug-design concept directed toward the development of antiinflammatory drugs that are lacking adverse ulcerogenic and/or cardiovascular effects. |
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