RESUMEN
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Asunto(s)
Nitrógeno/química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Semivida , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/farmacocinética , Ratas , SaimiriRESUMEN
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Broncoconstricción/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cobayas , Humanos , Concentración 50 Inhibidora , Inhibidores de Fosfodiesterasa/toxicidad , Quinolinas/toxicidad , Ratas , Saimiri , Ovinos , Relación Estructura-Actividad , Vómitos/inducido químicamenteRESUMEN
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacocinética , Isoenzimas/antagonistas & inhibidores , Piridazinas/síntesis química , Animales , Línea Celular , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Proteínas de la Membrana , Tasa de Depuración Metabólica , Prostaglandina-Endoperóxido Sintasas , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.