Harnessing GABA and NO mimetic activity for Alzheimer's therapy

利用 GABA 和 NO 模拟活性治疗阿尔茨海默病

• 批准号: 8111768
• 负责人: Gregory R. J Thatcher
• 金额: $ 34.61万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111768
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Aminobutyric Acids; Amyloid; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticonvulsants; Anus; Attenuated; Behavioral; Benchmarking; Biological Assay; Blood Pressure; Cell Culture Techniques; Cells; Characteristics; Chimera organism; Chlormethiazole; Clinical; Clinical Trials; Cognition; Cyclic GMP; Data; Development; Disease; Dose; Drug Design; Drug Kinetics; Elements; Funding; Future; Generations; Heminevrin; Hippocampus (Brain); Hypotension; In Vitro; Inflammatory; Lead; Legal patent; Libraries; Ligands; Literature; MAPK14 gene; Measurement; Methodology; Modeling; Molecular Structure; Mus; Neurodegenerative Disorders; Neurologic; Neurons; Neuroprotective Agents; Nitrates; Nitric Oxide; Partner in relationship; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Powder dose form; Process; Property; Rattus; Reporting; Research Personnel; Study models; Synapses; Toxicology; Transgenic Mice; Transgenic Organisms; Trees; United States National Institutes of Health; Water; analog; base; chimera drug; comparative; cytokine; design; drug candidate; functional restoration; gamma-Aminobutyric Acid; hypnotic; in vitro Assay; in vivo; microbial alkaline proteinase inhibitor; mimetics; mouse model; neuroprotection; novel; programs; prototype; receptor; restoration; scale up; sedative

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

描述（由申请人提供）：与衰老相关的神经退行性疾病在起源和进展上是多因素的，引起神经和精神异常。该项目基于这样的假设：一种药物在治疗神经/精神异常的同时减弱了几个潜在因素，是治疗阿尔茨海默病（AD）的首选疗法。GT-1061是一种完成了阿尔茨海默病（AD） IA期临床试验的新药物类别的原型；它结合了临床神经保护剂氯美唑（CMZ）和神经保护实验药物GT-015的结构元素。CMZ具有抗神经炎和模拟GABA等多种作用。GT-015是一种一氧化氮模拟物，具有包括认知增强在内的多效作用。我们提出一种结合NO模拟特性并利用CMZ的神经保护抗神经炎症和GABA模拟特性的分子可以优化为AD的疾病修饰和前认知剂。该提案的目的是利用CMZ类似物的小型集中合成文库，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，保留GABA模拟活性。将在AD转基因小鼠模型（AD- tg）中研究其体外和体内的神经保护作用。新的先导化合物，优化的CMZ类似物，将形成新的硝酸盐，NO嵌合体的结构基础，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检测cmz衍生的NO嵌合体的一个小文库，包括行为和组织学测量。为了获得该项目可交付的两种NO嵌合体候选药物，我们将在我们的药物设计策略中纳入来自以下方面的生物测定数据：动物模型中的镇静和前认知活性；理化性质、大体毒理学、药代动力学和对大鼠血压的影响。候选药物必须能够恢复AD-Tg小鼠的正常突触功能。最后，为GT-1061定义的预制剂策略将应用于2种新型NO嵌合体候选药物，以选择一种适合未来cGMP合成和ind前ADME/tox的候选药物

项目成果

Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.

• DOI: 10.1021/jm300353r
• 发表时间: 2012-08-09
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Qjn, Zhihui;Luo, Jia;VandeVrede, Lawren;Tavassoli, Ehsan;Fa', Mauro;Teich, Andrew F.;Arancio, Ottavio;Thatcher, Gregory R. J.
• 通讯作者: Thatcher, Gregory R. J.

A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.

• DOI: 10.1186/s13024-016-0103-6
• 发表时间: 2016-04-29
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Luo J;Lee SH;VandeVrede L;Qin Z;Ben Aissa M;Larson J;Teich AF;Arancio O;D'Souza Y;Elharram A;Koster K;Tai LM;LaDu MJ;Bennett BM;Thatcher GR
• 通讯作者: Thatcher GR