Harnessing GABA and NO mimetic activity for Alzheimer's therapy

描述(申请人提供)：神经退行性疾病，与衰老有关，在起源和发展上是多因素的，引起神经和精神异常。该项目基于这样一种假设，即一种在治疗神经/精神异常的同时减轻几个潜在因素的药物是治疗阿尔茨海默病(AD)的首选疗法。GT-1061是完成了治疗阿尔茨海默病(AD)的IA期临床试验的一种新药类别的原型；它包含了临床神经保护剂氯甲噻唑(CMZ)和神经保护实验药物GT-015的结构元素。CMZ具有多种作用，包括抗神经炎和GABA模拟作用。GT-015是一种一氧化氮(NO)模拟物，具有多种作用，包括增强认知能力。我们认为，一个没有模拟特性并利用CMZ的神经保护、抗神经炎和GABA模拟特性的分子可以被优化为AD的疾病改良剂和预知剂。该提案的目的是使用一个小型的有针对性的合成CMZ类似物文库，首先在细胞培养中进行测试，然后在动物模型中进行测试，以最大限度地提高抗炎特性，同时保留GABA模拟活性。体外和体内的神经保护将在AD转基因小鼠模型(AD-TG)中进行研究。新的先导化合物，优化的CMZ类似物，将形成新的硝酸盐的结构基础，没有嵌合体，旨在保留神经保护和GABA模拟活性，并增加辅助的NO模拟活性。将在细胞培养和动物模型中测试一个小的CMZ来源的非嵌合体文库，包括行为和组织学测量。为了实现这两个非嵌合体候选药物，我们将在我们的药物设计策略中纳入以下方面的生物分析数据：动物模型中的镇静剂和先兆认知活性；大鼠的物理化学性质、大体毒理学、药代动力学和血压效应。候选药物必须能够恢复AD-TG小鼠的正常突触功能。最后，将为GT-1061定义的预配方策略应用于两个新的非嵌合体候选药物，以便以适合于未来cGMP合成和前IND ADME/TOX的形式选择一个候选药物

DESCRIPTION (provided by applicant): Neurodegenerative diseases, associated with aging, are multifactorial in origin and progression, eliciting neurological and psychiatric abnormalities. This project is based upon the hypothesis that a drug attenuating several underlying factors whilst treating neurological/psychiatric abnormalities is a preferred therapy for Alzheimer's disease (AD). GT-1061 is a prototype of a new drug class that completed Phase IA clinical trials for Alzheimer's disease (AD); it incorporates structural elements of the clinical neuroprotective agent clomethiazole (CMZ) and the neuroprotective experimental drug, GT-015. CMZ has multiple actions including anti-neuroinflammatory and GABA mimetic. GT-015 is a NO (nitric oxide) mimetic that has pleiotropic actions including cognition enhancement. We propose that a molecule that incorporates NO mimetic properties and harnesses the neuroprotective anti-neuroinflammatory and GABA mimetic properties of CMZ can be optimized as a disease modifying and procognitive agent for AD. The objective of the proposal is to use a small focused synthetic library of CMZ analogs assayed first in cell culture and then in animal models to maximize the anti-inflammatory properties, retaining GABA mimetic activity. Neuroprotection in vitro and in vivo will be studied in a transgenic mouse model of AD (AD-Tg). The new lead compounds, optimized CMZ analogs, will form the structural basis for new nitrates, NO chimeras, designed to retain neuroprotective and GABA nmimetic activity and to add ancillary NO mimetic activity. A small library of CMZ-derived NO chimeras will be assayed in cell culture and in animal models, including behavioral and histological measurements. In order to arrive at the two NO chimera drug candidates that are deliverables from this project, we will incorporate into our drug design strategy bioassay data from: sedative and procognitive activity in animal models; physicochemical properties, gross toxicology, pharmacokinetics, and blood pressure effects in rats. The drug candidates must be able to restore normal synaptic funtion in AD-Tg mice. Finally, a preformulation strategy defined for GT-1061 will be applied to the 2 novel NO chimera drug candidates in order to select one candidate in a form suitable for future cGMP synthesis and pre-IND ADME/tox