RESUMEN
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Pirazoles/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Perros , Concentración 50 Inhibidora , Pirazoles/farmacología , 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
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Pirazoles/farmacología , Piridinas/farmacología , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Perros , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Pirazoles/síntesis química , Piridinas/síntesis químicaRESUMEN
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.