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: 9249890
• 负责人: Sharon Rosenzweig-Lipson
• 金额: $ 25万
• 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/9249890
• 关键词: Aging; Agonist; Alzheimer' s Disease; Animal Model; Animals; Binding; Brain; Characteristics; Chemicals; Clinic; Clinical; Cognition; Companions; Coupled; Data; Detection; Development; Dose; Drug Kinetics; Electrophysiology (science); Ensure; Formulation; Hippocampus (Brain); Human; In Vitro; Instruction; 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; mild cognitive impairment; normal aging; preclinical study; programs; receptor; response; safety study

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 a5 receptor agonists are effective therapeutic agents to improve memory. We have identified several different chemical series that are selective for GABAA a5 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 a5 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 a5 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 a5 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 a5 receptor agonist filing with the FDA. RELEVANCE (See instructions):

该U 01申请的总体目标是开发一种口服活性的、优化的先导化合物， 治疗遗忘型轻度认知障碍（aMCI）。提出的治疗方法是基于观察 aMCI是介于正常衰老和阿尔茨海默病（AD）之间的一种临界状态， 与海马CA 3/齿状回（DG）区域的过度活动相关。削减过剩 活动，或使其正常化，有望改善这些患者的记忆力。动物临床前研究 这种情况的模型，其中海马CAS神经元在记忆丧失的老年大鼠中过度活跃， 表明选择性GABAA α 5受体激动剂是有效的治疗剂，以改善 记忆我们已经鉴定了对GABAA α 5受体具有选择性的几种不同的化学系列。 这些系列中的化合物最初是由大型制药公司开发的， 反向激动剂活性，目的是改善认知。这种方法在 事实上，支持我们所提出的工作的科学将预测这种方法将失败。仍 这些化学系列具有药物样性质 受体激动剂在特定目标下，我们将在药物化学中使用已建立的体外试验 优化对含有GABAA α 5亚基的受体的选择性和激动剂功效的程序， 早期的ADME和毒理学工作，以确定对动物给药的适用性。体内研究将 然后在衰老中记忆丧失的动物模型中进行，该模型反映了在老年人中观察到的许多特征。 人类，尤其是aMCI。使用多种方法测定体内受体结合率的伴随研究 还将使用液相色谱-串联质谱检测（LC/MS/MS）示踪剂， 进行以验证靶GABAA α 5受体的接合以及对该受体的选择性 亚型，在行为上有效的剂量下。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，良好的生产规范（GMP）合成， GABAA α 5受体激动剂的主要制剂。 相关性（参见说明）：