RESUMEN
Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Éteres/química , Pirazoles/síntesis química , Pirazoles/farmacología , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Alquilación , Animales , Inhibidores de la Ciclooxigenasa 2/sangre , Inhibidores de la Ciclooxigenasa 2/química , Perros , Concentración 50 Inhibidora , Estructura Molecular , Pirazoles/sangre , Pirazoles/química , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/química , Triazoles/sangre , Triazoles/químicaRESUMEN
Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Éteres/química , Pirazoles/química , Compuestos de Sulfhidrilo/química , Alquilación , Animales , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Perros , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2/efectos de los fármacos , Pirazoles , Administración Oral , Animales , Gatos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.