RESUMO
Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/síntese química , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Concentração Inibidora 50 , Maleimidas/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Proteínas tau/metabolismoRESUMO
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Imidazóis/síntese química , Piridinas/síntese química , Pirróis/síntese química , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos ZuckerRESUMO
Developing countries are already benefiting and should continue to benefit significantly from advances in plant biotechnology. Insect-protected cotton containing a natural insecticide protein from Bacillus thuringiensis (Bt cotton) is providing millions of farmers with increased yields, reduced insecticide costs and fewer health risks. Many other useful plant biotechnology products that can benefit poor farmers and consumers are in the research and development pipelines of institutions in developing countries, and should soon reach farmers' fields.
