RESUMO
A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.
Assuntos
Antipirina/análogos & derivados , Vasodilatadores/síntese química , Animais , Antipirina/síntese química , Antipirina/química , Antipirina/farmacocinética , Estabilidade de Medicamentos , Edaravone , Humanos , Nitratos/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacocinética , Nitritos/metabolismo , Permeabilidade , Ratos , Vasodilatadores/química , Vasodilatadores/farmacocinéticaRESUMO
Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.
