RESUMO
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
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
Assuntos
Antitrombina III/síntese química , Inibidores do Fator Xa , Corantes Fluorescentes/farmacologia , ortoaminobenzoatos/farmacologia , Anticoagulantes/química , Antitrombina III/química , Sítios de Ligação , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/síntese química , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese químicaRESUMO
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).