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 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.
Asunto(s)
Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/química , Isoenzimas/antagonistas & inhibidores , Piridinas/administración & dosificación , Piridinas/química , Administración Oral , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Perros , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Relación Estructura-ActividadRESUMEN
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Animales , Bovinos , Enfermedades de los Bovinos/microbiología , Femenino , Hormona Liberadora de Gonadotropina/síntesis química , Mastitis Bovina/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Pasteurella multocida/efectos de los fármacos , Pasteurelosis Neumónica/microbiología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria.