RESUMO
New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives, were designed by modeling, synthesized and evaluated in vitro. Compound 17c showed good potency in enzyme and cell-based assays (IC50=111 nM, EC50=1.78 µM). Moreover, it has demonstrated desirable water solubility, PK profile, and moderate brain penetration.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridonas/síntese química , Piridonas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine kinase also known as tau protein kinase I, has been implicated in the pathogenic conditions of Alzheimer's disease. Many investigators have focused on GSK-3 inhibitor as a therapeutic drug. In this study, we established a cell-based assay for the screening of novel GSK-3ß inhibitors. For this purpose, four-repeat tau cDNAs were stably expressed in human embryonic kidney 293 (HEK293) cells (HEK293-Tau). The proliferation of HEK293-Tau cells was no different from that of HEK293 cells, as measured by the bromodeoxyuridine enzyme-linked immunosorbent assay (BrdU ELISA). The concentration-dependent reduction of tau phosphorylation by GSK-3 inhibitors, LiCl, Chir98023, and SB415286, was examined by immunoblot analysis and Tau ELISA (in situ ELISA). Highly consistent data were obtained, suggesting that this novel ELISA method is highly reproducible. Using this ELISA strategy, we isolated a few candidate compounds, including compounds 114 and 149, from several hundreds of synthetic agents and demonstrated that such candidates protect nerve growth factor-differentiated PC12 cells against amyloid-ß-induced cell death. These data indicate that this Tau ELISA method in HEK293-Tau cells may be a suitable cell-based assay system to screen for GSK-3ß inhibitors.
Assuntos
Doença de Alzheimer/enzimologia , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Aminofenóis/análise , Aminofenóis/metabolismo , Aminofenóis/farmacologia , Aminofenóis/toxicidade , Animais , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/toxicidade , Ensaio de Imunoadsorção Enzimática , Quinase 3 da Glicogênio Sintase/análise , Quinase 3 da Glicogênio Sintase/fisiologia , Células HEK293 , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Immunoblotting , Maleimidas/análise , Maleimidas/metabolismo , Maleimidas/farmacologia , Maleimidas/toxicidade , Terapia de Alvo Molecular , Fármacos Neuroprotetores/análise , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/toxicidade , Células PC12 , Fosforilação/fisiologia , Plasmídeos , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Ratos , Proteínas tau/metabolismoRESUMO
Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo T/efeitos dos fármacos , Morfolinas/síntese química , Morfolinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Linhagem Celular , Humanos , Concentração Inibidora 50 , Oócitos , Relação Estrutura-Atividade , XenopusRESUMO
[reaction: see text] A new and efficient indium-mediated one-pot three-component reaction for the synthesis of N-aryl-substituted homoallylamines from aromatic amines, enol ethers, and allylic bromides in THF at room temperature is described.
