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.
Subject(s)
Alzheimer Disease/drug therapy , Drug Development/methods , tau Proteins/drug effects , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Humans , Patents as Topic , tau Proteins/metabolismSubject(s)
Alzheimer Disease/pathology , tau Proteins/antagonists & inhibitors , Acetylation , Alzheimer Disease/drug therapy , Animals , Humans , Methylene Blue/analogs & derivatives , Methylene Blue/therapeutic use , Mice , Salicylates/therapeutic use , Severity of Illness Index , tau Proteins/metabolismABSTRACT
AIM: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab ((131)I-rituximab) for treating Korean patients with relapsed or refractory B-cell non-Hodgkin's lymphomas (NHL). METHODS: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of (131)I-rituximab. The tumor response was evaluated 1 month later by contrast enhanced (18) F-fludeoxyglucose positron emission tomography-computed tomography. RESULTS: Between May 2004 and October 2006, 24 patients received single treatment with (131)I-rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B-cell NHL (LGL) and 9% (one PR) for patients with diffuse large B-cell lymphoma (DLBCL). After a median follow-up of 55 months, the median progression-free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3-4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. CONCLUSION: RIT with (131)I-rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of (131)I-rituximab for treating the patients with DLBCL.