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迟其发作或减缓其进展。我们已经开发了一种新型的类药物小分子化合物，其特异性靶向AD受影响的神经元表达的细胞表面受体，称为p75受体。这些p75受体配体激活存活促进信号传导并抑制p75受体的退化促进信号传导。在组织培养研究中，这些配体能够阻断淀粉样蛋白β（A？）激活受AD影响的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下，并且已经证实通过它们在p75的作用发生。此外，我们的配体阻断了A？寡聚体的毒性，A？种类被认为对神经元毒性最大，与AD最相关。在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到达大脑，并且已被发现没有毒性作用，包括肝脏，心脏和DNA毒性研究。在这些小鼠中，我们的先导化合物显示出逆转或预防人类和啮齿动物系统中衰老和AD期间发生的基底前脑胆碱能萎缩的显著神经营养作用。在充分表征的AD小鼠模型的初步试验中，我们的先导化合物似乎改善了记忆功能，并减少了AD的典型病理特征。在本申请中，我们将完成以下三个里程碑驱动的项目：i）验证阿尔茨海默病小鼠的疗效和评估潜在的机制为基础的副作用; ii）cGMP放大合成和纯度所需的研究新药（IND）申请到FDA;和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，以进行第一次人体I期试验。该项目的完成还将建立一个新的化学实体（NCE）和一种新型的、首个用于开发AD治疗药物的药物化合物。

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.