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
A highly effective protocol for palladium-catalyzed selective arylation and heteroarylation of indolizines at C-3 has been developed. Mechanistic studies unambiguously support an electrophilic substitution pathway for this transformation.
