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

描述（由申请人提供）：本U 01申请的总体目标是开发一种口服活性的优化先导化合物，用于治疗遗忘型轻度认知障碍（aMCI）。所提出的疗法是基于以下观察结果：aMCI（正常衰老和阿尔茨海默病（AD）之间的边界条件）中的记忆丧失与海马体的CA 3/齿状回（DG）区域中的过度活动相关。减少过度活动或使其正常化，有望改善这些患者的记忆力。在这种情况下，海马CAS神经元是过度活跃的老年大鼠记忆丧失的动物模型的临床前研究表明，选择性GABAA？5受体激动剂是改善记忆的有效治疗剂。我们已经确定了几个不同的化学系列，是选择性的GABAA？5个受体。这些系列中的化合物最初由大型制药公司开发，以优化反向激动剂活性，目的是改善认知。这种方法在临床上并不有效;事实上，支持我们所提出的工作的科学会预测这种方法会失败。这些化学系列仍然具有药物样性质，为选择性优化提供了起点？5受体激动剂。根据具体的目标，我们将使用建立在药物化学程序中的体外测定，以优化GABAA的选择性和激动剂功效？5亚基的受体，并进行早期ADME和毒理学工作，以确定对动物给药的适用性。然后将在衰老中记忆丧失的动物模型中进行体内研究，该模型反映了在老年人中观察到的许多特征，特别是aMCI。还将进行伴随研究，以确定使用多种示踪剂与液相色谱串联质谱检测（LC/MS/MS）结合的体内受体占有率，以验证目标GABAA的参与？5受体，以及对该受体亚型的选择性。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）的合成和制定铅GABAA？5受体激动剂在FDA备案。

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.