P75 Small Molecule Ligands for Alzheimer's Therapy

用于阿尔茨海默病治疗的 P75 小分子配体

基本信息

批准号：
7910427
负责人：
FRANK M LONGO
金额：
$ 85.01万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910427
关键词：
ADME Study Acute Adverse effects Affect Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Area Atrophic Biochemical Brain Canis familiaris Cardiac Cardiovascular system Categories Cell Surface Receptors Chemicals Cholinergic Fibers Clinical Trials Design Cognitive DNA Development Dose Drug Compounding Excretory function Goals Guidelines Hepatic Human Hypertrophy Investigational Drugs Investigational New Drug Application Kilogram Kinetics Lead Ligands Measures Memory Memory Loss Metabolism Modeling Mus Mutant Strains Mice NGFR Protein National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurons New Drug Approvals Oral Administration Outcome Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology and Toxicology Phase Phase I Clinical Trials Pilot Projects Plasma Play Preparation Protein Binding Protocols documentation Rattus Research Design Research Personnel Rodent Role Route Safety Schedule Signal Transduction Staging System Testing Therapeutic Time Toxic effect Toxicology absorption allodynia basal forebrain basal forebrain cholinergic neurons base cell growth cholinergic cognitive function density genotoxicity good laboratory practice improved meetings middle age morris water maze mouse model neoplastic cell novel object recognition pilot trial prevent programs protective effect receptor respiratory scale up small molecule tissue culture transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that leads to the progressive loss of memory and other cognitive functions. At this time, there are no approved treatments that are capable of delaying its onset or slowing its progression. We have developed a novel category of drug-like, small molecule compounds that specifically target a cell surface receptor that is expressed by neurons affected in AD, known as the p75 receptor. These p75 receptor ligands activate survival-promoting signaling and inhibit degenerative-promoting signaling of the p75 receptor. In tissue culture studies, these ligands are capable of blocking the ability of amyloid beta (A¿) to activate degenerative signaling within neurons affected in AD. The protective effects of these compounds occur at low nanomolar concentrations and have been verified to occur through their action at p75. Moreover, our ligands block the toxicity of A¿ oligomers, the A¿ species thought to be most toxic to neurons and most relevant to AD. In studies of normal middle aged mice, our lead compound has been demonstrated to reach the brain following daily oral administration and has been found to have no toxic effects including studies of hepatic, cardiac and DNA toxicity. In these mice, our lead compound demonstrates a significant neurotrophic effect of reversing or preventing basal forebrain cholinergic atrophy of the type that occurs during aging and AD in both human and rodent systems. In pilot trials in a well characterized AD mouse model, our lead compound appears to be improving memory function and to be reducing pathological features typical of AD. In this application we will complete the following three milestone-driven projects: i) verification of efficacy in Alzheimer's mice and assessment of potential mechanism-based side effects; ii) cGMP scaled up synthesis and purity necessary for an Investigational New Drug (IND) application to the FDA; and iii)toxicology and pharmacology studies designed to complete an IND application. Completion of these three projects will allow an IND application with the overall goal of obtaining IND approval for conducting the first Phase I trials humans. Completion of the proposed project will also establish a new chemical entity (NCE) and a novel, first in class, drug compound for development in AD therapeutics.

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，会导致记忆和其他认知功能进行性丧失。目前，尚无批准的治疗方法能够延迟其发病或减缓其进展。我们开发了一种新型药物样小分子化合物，专门针对 AD 中受影响的神经元表达的细胞表面受体，即 p75 受体。这些 p75 受体配体可激活促进生存的信号传导并抑制。在组织培养研究中，这些配体能够阻断淀粉样蛋白 (A¿) 激活受 AD 影响的神经元内的退行性信号传导，这些化合物在低纳摩尔浓度下即可发挥保护作用。并且已被证实通过其在 p75 上的作用而发生。此外，我们的配体可阻断 A¿ 的毒性。寡聚物，A¿在对正常中年小鼠的研究中，我们的先导化合物已被证明在每日口服给药后能够到达大脑，并且发现没有毒性作用，包括对肝脏、中年小鼠的研究。在这些小鼠中，我们的先导化合物在人类和啮齿类动物系统中进行的初步试验中显示出显着的神经营养作用，可以逆转或预防在衰老和 AD 过程中发生的基底前脑胆碱能萎缩。模型，我们的先导化合物似乎可以改善记忆功能并减少 AD 的典型病理特征。在该应用中，我们将完成以下三个里程碑驱动的项目：i) 验证阿尔茨海默病小鼠的功效并评估潜在的基于机制的副作用。 ii) 向 FDA 申请研究新药 (IND) 所需的 cGMP 扩大合成和纯度；以及 iii) 旨在完成 IND 申请的毒理学和药理学研究将允许整体 IND 申请。获得的目标IND 批准进行首次人体 I 期试验，该项目的完成还将建立一个新的化学实体 (NCE) 和一种用于 AD 治疗开发的新型一流药物化合物。