Development of a lead candidate for the treatment of Alzheimer's disease

开发治疗阿尔茨海默病的主要候选药物

基本信息

批准号：
10706549
负责人：
Corinne Ida Lasmezas
金额：
$ 10.03万
依托单位：
VOVA IDA THERAPEUTICS INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706549
关键词：
Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Area Behavioral Binding Biochemical Biological Assay Biological Availability Biological Markers Blood Circulation Brain Cause of Death Cell Survival Cell surface Cells Complex Cytochrome P450 Degradation Pathway Depressed mood Development Disease Dose Drug Kinetics Drug Targeting Enzymes Epidemic Evaluation Event Exposure to Florida Functional disorder G-Protein-Coupled Receptors Goals Half-Life Health Human Hydrogen Bonding In Vitro Intellectual Property Ion Channel Knock-in Lead Liver Microsomes Mediator Membrane Proteins Memory Metabolic Monitor Mus Neurons Oral Oxidative Stress Pathogenicity Pathology Patients Penetration Peptides Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Plasma Positioning Attribute PrP Property Protein Isoforms Rodent Safety Series Signal Transduction Societies Specificity Structure-Activity Relationship Surface Symptoms Synapses Testing Therapeutic Therapeutic Intervention Toxic effect United States Work age related neurodegeneration analog bioinformatics tool chemical synthesis clinical development drug metabolism excitotoxicity high throughput screening immunocytochemistry improved in silico in vivo induced pluripotent stem cell lead candidate lead optimization meter mitochondrial dysfunction neuroblastoma cell neuropathology neurotoxic novel novel lead compound novel therapeutic intervention pharmacologic preclinical development presenilin-1 receptor response screening panel small molecule targeted treatment tau Proteins therapeutic evaluation

项目摘要

SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disease that has become a global epidemic with over 40 million people affected worldwide and a projected 115 million in 2050. It is the 6th leading cause of death in the United States. AD has a tremendous impact on health, society and the economy. Approved treatments at best partially ameliorate some symptoms. There is an urgent need for novel, disease-modifying treatments. AD is a complex disease with multiple players that may be targeted for therapeutic intervention. A core pathogenic mechanism is the cellular toxicity of Ab42 peptide oligomers with the cascade of activation and phosphorylation events that follow neuronal oligomeric Ab42 binding and internalization. These result, inter alia, in oxidative stress, mitochondrial dysfunction, synaptic dysfunction, abnormal Ca2+ signaling and excitotoxicity. The overarching goal of this project is to develop a drug targeting neurotoxic Ab42 signaling. In this phase 1 component of the project, we will demonstrate the feasibility of optimizing our candidate compound into a therapeutic lead. We will conduct several rounds of structure-activity relationship studies aimed at increasing the compound’s potency, selectivity, metabolic and pharmacokinetic properties, including brain penetration. A series of in vitro/cell-based assays, DMPK studies and testing in a murine AD model will guide compound progression. The successful completion of phase 1 will deliver an optimized lead compound ready for development and IND-enabling studies in phase 2.

概括阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，已成为全球性的疾病该流行病在全球范围内影响了超过 4000 万人，预计到 2050 年将有 1.15 亿人受到影响。这是第六次 AD 对健康、社会和社会产生巨大影响。批准的治疗最多只能部分改善某些症状。新颖的疾病缓解疗法是一种复杂的疾病，可能涉及多个参与者。治疗干预的核心致病机制是 Ab42 肽寡聚物的细胞毒性。神经元寡聚 Ab42 结合后发生一系列激活和磷酸化事件这些结果尤其导致氧化应激、线粒体功能障碍、突触。该项目的首要目标是开发功能障碍、异常 Ca2+ 信号传导和兴奋性毒性。一种针对神经毒性 Ab42 信号传导的药物在该项目的第一阶段部分，我们将展示。将我们的候选化合物优化为治疗先导药物的可行性我们将进行多项研究。多轮结构活性研究旨在提高化合物的效力、选择性、代谢和药代动力学特性，包括脑渗透一系列基于体外/细胞的特性。小鼠 AD 模型中的测定、DMPK 研究和测试将指导化合物的进展。第一阶段的成功完成将提供一种优化的先导化合物，可供开发和使用第二阶段的 IND 支持研究。