RESUMO
Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-ß (Aß) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aß-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Camundongos , Mitocôndrias/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Regulador Transcricional ERG/antagonistas & inibidores , Regulador Transcricional ERG/metabolismoAssuntos
Doença de Alzheimer/patologia , Proteínas tau/antagonistas & inibidores , Acetilação , Doença de Alzheimer/tratamento farmacológico , Animais , Humanos , Azul de Metileno/análogos & derivados , Azul de Metileno/uso terapêutico , Camundongos , Salicilatos/uso terapêutico , Índice de Gravidade de Doença , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss and cognitive impairment. As this disease is becoming a serious global health issue, development of disease modifying therapeutics is urgently required. AD is characterized by deposits of two protein, amyloid ß and tau. Although amyloid ß-based therapeutics have been extensively investigated so far, tau has also received great attention as one of promising molecular targets for AD. In this review, a variety of tau-directed strategies to rescue tau-mediated neurotoxicity will be reviewed especially focusing on small molecules. Subsequently, recent patents published from 2014 to 2018 that integrate efforts to develop tau-directed small molecules for the treatment of AD will be reviewed.
