RESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Éteres/química , Pirazóis/síntese química , Pirazóis/farmacologia , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Alquilação , Animais , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/química , Cães , Concentração Inibidora 50 , Estrutura Molecular , Pirazóis/sangue , Pirazóis/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/química , Triazóis/sangue , Triazóis/químicaRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2/efeitos dos fármacos , Pirazóis , Administração Oral , Animais , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Éteres/química , Pirazóis/química , Compostos de Sulfidrila/química , Alquilação , Animais , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Cães , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.