ABSTRACT
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.
Subject(s)
Alzheimer Disease/drug therapy , Mitochondria/drug effects , Neuroprotective Agents/pharmacology , Protein Aggregation, Pathological/drug therapy , Small Molecule Libraries/pharmacology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Ligands , Mice , Mitochondria/metabolism , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
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.