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的起源和进展是多因素的，会引起神经和精神异常。该项目基于这样的假设：在治疗神经/精神异常的同时减轻多种潜在因素的药物是阿尔茨海默病 (AD) 的首选疗法。 GT-1061是一类新药的原型，已完成阿尔茨海默病（AD）的IA期临床试验；它结合了临床神经保护剂氯美噻唑（CMZ）和神经保护实验药物 GT-015 的结构元件。 CMZ 具有多种作用，包括抗神经炎症和 GABA 模拟物。 GT-015 是一种 NO（一氧化氮）模拟物，具有包括认知增强在内的多效性作用。我们提出，结合 NO 模拟特性并利用 CMZ 的神经保护性抗神经炎症和 GABA 模拟特性的分子可以被优化为 AD 的疾病缓解和认知剂。该提案的目的是使用一个小型集中合成的 CMZ 类似物文库，首先在细胞培养物中进行检测，然后在动物模型中进行检测，以最大限度地提高抗炎特性，同时保留 GABA 模拟活性。将在 AD 转基因小鼠模型 (AD-Tg) 中研究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，并添加辅助的 NO 模拟活性。 CMZ 衍生的 NO 嵌合体的小型文库将在细胞培养物和动物模型中进行分析，包括行为和组织学测量。为了获得该项目的两种 NO 嵌合体候选药物，我们将把来自以下方面的生物测定数据纳入我们的药物设计策略：动物模型中的镇静和促认知活性；理化性质、总体毒理学、药代动力学和对大鼠的血压影响。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 定义的预配制策略将应用于 2 种新型 NO 嵌合体候选药物，以便选择一种适合未来 cGMP 合成和预 IND ADME/tox 形式的候选药物

项目成果

Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy.

调节中枢神经系统中的一氧化氮信号传导以治疗阿尔茨海默病。

• DOI: 10.4155/fmc.13.111
• 发表时间: 2013-08-07
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: Zhihui Qin

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

神经保护性甲基噻唑的设计和合成以及修饰为用于神经退行性治疗的 NO 嵌合体。

• 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.

一种在多个家族小鼠模型和阿尔茨海默病的新型散发模型中进行疾病修饰的多功能治疗方法。

• 发表时间: 2016-04-29
• 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