RESUMO
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.
Assuntos
Nitrogênio/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/farmacocinética , Ratos , SaimiriRESUMO
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.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cobaias , Humanos , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/toxicidade , Quinolinas/toxicidade , Ratos , Saimiri , Ovinos , Relação Estrutura-Atividade , Vômito/induzido quimicamenteRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacocinética , Isoenzimas/antagonistas & inibidores , Piridazinas/síntese química , Animais , Linhagem Celular , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Proteínas de Membrana , Taxa de Depuração Metabólica , Prostaglandina-Endoperóxido Sintases , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.