P75 Small Molecule Ligands for Alzheimer's Therapy

描述(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，还没有得到批准的治疗方法能够延缓其发病或减缓其进展。我们已经开发了一种新的类药物小分子化合物，它专门针对AD患者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p75受体的促存活信号，抑制p75受体的退变促进信号。在组织培养研究中，这些配体能够阻断淀粉样β蛋白(A？)激活AD影响的神经元内退化信号的能力。这些化合物的保护作用在低纳摩尔浓度下发生，并已被证实通过它们在p75的作用而发生。此外，我们的配体还能阻止A低聚物的毒性，A低聚物被认为是对神经元毒性最大的物种，与AD关系最大。在对正常中年小鼠的研究中，我们的化合物已被证明在每天口服后到达大脑，并被发现没有毒性作用，包括肝脏、心脏和DNA毒性的研究。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，可以逆转或防止人类和啮齿动物系统在衰老和AD期间发生的基底前脑胆碱能萎缩。在一个特征良好的AD小鼠模型的试点试验中，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。在这项应用中，我们将完成以下三个里程碑式的项目：i)对阿尔茨海默氏症小鼠的疗效验证和潜在的基于机制的副作用评估；ii)cGMP扩大合成和纯度，这是向FDA提出研究性新药(IND)申请所必需的；以及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，总体目标是获得IND的批准，进行第一阶段的人类试验。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AD治疗的开发。

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.