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
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Assuntos
Benzamidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Triazóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.