GABA-A alpha-5 agonists for the treatment of amnestic Mild Cognitive Impairment

GABA-A α-5 激动剂用于治疗遗忘性轻度认知障碍

• 批准号: 8221932
• 负责人: Michela Gallagher
• 金额: $ 42.38万
• 依托单位: AGENEBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8221932
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Aging; Agonist; Alzheimer' s Disease; Animal Model; Animals; Binding; Brain; Characteristics; Chemicals; Clinic; Clinical; Cognition; Companions; Coupled; Data; Detection; Development; Dose; Drug Formulations; Drug Kinetics; Ensure; Hippocampus (Brain); Human; In Vitro; Lead; Libraries; Liquid Chromatography; Literature; Measures; Memory; Memory Loss; Memory impairment; Neurons; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Principal Investigator; Property; Rattus; Research; Research Contracts; Science; Series; Site; Structure-Activity Relationship; Testing; Therapeutic Agents; Toxicology; Tracer; Work; aged; base; dentate gyrus; design; drug candidate; gamma-Aminobutyric Acid; improved; in vitro Assay; in vivo; innovation; lead series; liquid chromatography mass spectrometry; meetings; microbial alkaline proteinase inhibitor; mild neurocognitive impairment; normal aging; preclinical study; programs; receptor; response; safety study

DESCRIPTION (provided by applicant): The overall objective of this U01 application is to develop an orally active, optimized lead compound for the treatment of amnestic mild cognitive impairment (aMCI). The proposed therapy is based on the observation that memory loss in aMCI, a borderline condition between normal aging and Alzheimer's Disease (AD), is associated with excess activity in the CA3/dentate gyrus (DG) region of the hippocampus. Reducing excess activity, or normalizing it, is expected to improve memory in these patients. Preclinical studies in an animal model of this condition, in which hippocampal CAS neurons are hyperactive in aged rats with memory loss, demonstrates that selective GABAA ?5 receptor agonists are effective therapeutic agents to improve memory. We have identified several different chemical series that are selective for GABAA ?5 receptors. Compounds within these series were originally developed by large pharmaceutical companies to optimize inverse agonist activity with the objective of improving cognition. This approach was not efficacious in the clinic; indeed the science supporting our proposed work would predict that such an approach would fail. Still these chemical series have drug like properties that provide a starting point for optimization of selective ?5 receptor agonists. Under the specific aims we will use established in vitro assays in a medicinal chemistry program to optimize selectivity and agonist efficacy for GABAA ?5 subunit containing receptors and conduct early ADME and toxicology work to determine suitability for administration to animals. In vivo studies will then be performed in an animal model of memory loss in aging that mirrors many features observed in aged humans, particularly aMCI. Companion studies to determine in vivo receptor occupancy using multiple tracers with liquid chromatography coupled to tandem mass spectral detection (LC/MS/MS) will also be conducted to validate engagement of target GABAA ?5 receptors, as well as selectivity for that receptor subtype, at doses that are behaviorally efficacious. In the final phase of the project we will complete all materials, including pharmacokinetics and toxicology, good manufacturing practice (GMP) synthesis and formulation for lead GABAA ?5 receptor agonist filing with the FDA.

描述（由申请人提供）：该U01应用的总体目的是开发一种口服活跃的优化铅化合物，用于治疗柔性轻度认知障碍（AMCI）。拟议的治疗是基于这样的观察结果：AMCI的记忆丧失是正常衰老和阿尔茨海默氏病之间的边缘条件（AD）与海马的CA3/齿状回（DG）区域的过量活动有关。预计减少过量活动或使其归一化的活动有望改善这些患者的记忆力。在这种情况的动物模型中，海马CAS神经元在老年大鼠中具有多动的临床前研究表明，有选择性的GABAA？5受体激动剂是有效的治疗剂来改善记忆记忆。我们已经确定了几个针对GABAA？5受体选择性的化学系列。这些系列中的化合物最初是由大型制药公司开发的，以优化反向激动剂活动，目的是改善认知。这种方法在诊所没有有效。实际上，支持我们拟议的工作的科学将预测这种方法将失败。这些化学系列仍然具有像药物一样的特性，可以优化选择性？5受体激动剂的起点。在具体目的下，我们将在药物化学计划中使用已建立的体外测定法，以优化含有受体的GABAA的选择性和激动剂功效，并进行早期的ADME和毒理学工作，以确定对动物的适用性。然后将在体内研究中进行体内研究，以衰老的记忆力丧失模型，反映了在年龄人类（尤其是AMCI）中观察到的许多特征。还将进行伴侣研究，以使用多个具有液相色谱的示踪剂来确定与串联质谱检测（LC/MS/MS）耦合的多个示踪剂（也将进行验证靶GABAA？5受体的参与度，以及该受体亚型的选择性，并以行为有效的剂量进行剂量。在项目的最后阶段，我们将完成所有材料，包括药代动力学和毒理学，良好的制造实践（GMP）合成和铅GABAA的配方？5向FDA提交的受体激动剂。