RESUMO
Seeking neutral sphingomyelinase inhibitors, we designed and synthesized hydrolytically stable analogues of sphingomyelin. These novel analogues replace the phosphodiester moiety of sphingomyelin with carbamate and urea moiety, resulting in inhibition of neutral sphingomyelinase. Compound 1 prevented ceramide generation and apoptotic neuronal cell death in a model of ischemia based on organotypic hippocampal slice cultures.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Ceramidas/síntese química , Ceramidas/farmacologia , Inibidores Enzimáticos/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Marcação In Situ das Extremidades Cortadas , Indicadores e Reagentes , Microssomos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Relação Estrutura-AtividadeRESUMO
To search for neutral sphingomyelinase inhibitors we designed and synthesized hydrolytically stable analogues of sphingomyelin. The novel compounds 8 and 9 which were replaced the phosphodiester moiety of sphingomyelin with the carbamate moiety showed inhibitory activity with an IC(50) value of micro M on neutral sphingomyelinase in rat brain microsomes. Compound 8i showed a selective neutral sphingomyelinase inhibitory activity.