RESUMO
Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3ß inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44 nM) against glycogen synthase kinase 3ß (GSK3ß). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3ß, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3ß inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse.
Assuntos
Aminopiridinas/síntese química , Desenho de Fármacos , Hipoglicemiantes/síntese química , Imidazóis/química , Imidazóis/síntese química , Piridinas/química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Sítios de Ligação , Glicemia/análise , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos/metabolismo , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Design, synthesis and the GSK3ß inhibitory activities of the 7-hydroxy benzimidazole analogs are described. The solid-phase synthetic route was also developed for preparation of the analogs consisting of the novel ATP competitive scaffold. In addition, the structure-activity relationship of the 7-hydroxy benzimidazole analogs and their biological activities are reported.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Quinase 3 da Glicogênio Sintase/química , Glicogênio Sintase Quinase 3 beta , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Histone deacetylase plays an important role in HIV latency. Novel histone deacetylase inhibitors, CG05 and CG06, were evaluated for their roles in HIV latency using ACH2 cells. Both inhibitors were highly efficient in reactivation of provirus and exerted lesser toxicity compared with other known histone deacetylase inhibitors. Histone acetylation increased when proviruses were reactivated by the compounds. These new inhibitors may contribute to the reduction of the HIV reservoir when used in conjunction with highly active antiretroviral therapy.
