RESUMO
The synthesis, structure-activity relationship and modeling of a series of 5-substituted-N-aryl pyridazinone based p38alpha inhibitors are described. In comparing the series to the similar N-aryl pyridinone series, it was found that the pyridazinones maintained a weaker interaction to the p38 enzyme, and therefore showed generally weaker binding than the pyridinones.
Assuntos
Anti-Infecciosos/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridazinas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Sítios de Ligação , Simulação por Computador , Descoberta de Drogas , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Domínio Catalítico , Humanos , Modelos Moleculares , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.