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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Proteínas tau/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Patentes como Assunto , Proteínas tau/metabolismoRESUMO
We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then screened in vitro against panel of susceptible and resistant Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis (Mtb). Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against the tested bacteria. Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis. Selected compound 10b showed good human microsomal stability and CYP-profile, and showed low activity against hERG channel.
