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
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.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Furanos/síntesis química , Furanos/farmacología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Células CHO , Fenómenos Químicos , Química Física , Cricetinae , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Edema/inducido químicamente , Edema/prevención & control , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Humanos , Proteínas de la Membrana , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Solubilidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.