RESUMO
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
Assuntos
Inibidores Enzimáticos/farmacologia , Naftiridinas/química , Piperidinas/química , Quinolonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite Experimental , Colágeno/química , Dexametasona/química , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/metabolismo , Camundongos , Modelos Químicos , Ratos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Development for a class of potent 3,4-dihydropyrido(3,2-d)pyrimidone inhibitors of p38a MAP kinase is described. Modification of N-1 aryl and C-6 arylsulfide in 3,4-dihydropyrido(3,2-d)pyrimidone analogues for the interaction with the hydrophobic pockets in p38 active site is also discussed.
Assuntos
Inibidores Enzimáticos/síntese química , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pirimidinonas/síntese química , Inibidores Enzimáticos/farmacologia , Cinética , Estrutura Molecular , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Desenho de Fármacos , Indicadores e Reagentes , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).
