P75 Small Molecule Ligands for Alzheimer's Therapy

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，导致记忆力和其他认知功能的进行性丧失。目前，还没有批准的治疗方法能够延缓其发病或减缓其进展。我们已经开发出一种新的类药小分子化合物，专门针对阿尔茨海默病中受影响的神经元表达的细胞表面受体，即p75受体。这些p75受体配体激活促生存信号传导并抑制p75受体的促退化信号传导。在组织培养研究中，这些配体能够阻断β淀粉样蛋白（A¿）激活阿尔茨海默病神经元内退行性信号传导的能力。这些化合物的保护作用发生在低纳摩尔浓度，并已通过它们在p75的作用得到证实。此外，我们的配体阻断了A -寡聚物的毒性，A -寡聚物被认为对神经元毒性最大，与AD最相关。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后可以到达大脑，并且在肝脏、心脏和DNA毒性研究中没有发现任何毒性作用。在这些小鼠中，我们的先导化合物显示出显著的神经营养作用，可以逆转或预防人类和啮齿动物系统中在衰老和AD期间发生的基底前脑胆碱能萎缩。在一个特征良好的阿尔茨海默病小鼠模型的初步试验中，我们的先导化合物似乎可以改善记忆功能并减少阿尔茨海默病的典型病理特征。在此申请中，我们将完成以下三个里程碑驱动的项目：i)验证阿尔茨海默氏症小鼠的疗效和评估潜在的基于机制的副作用；ii) cGMP扩大了向FDA申请新药（IND）所需的合成和纯度；iii)毒理学和药理学研究，旨在完成IND申请。这三个项目的完成将允许IND申请，其总体目标是获得IND批准进行第一阶段人体试验。拟议项目的完成还将建立一个新的化学实体（NCE）和一个新的，一流的药物化合物，用于开发阿尔茨海默病治疗方法。

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.