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

描述（由申请人提供）：该 U01 申请的总体目标是开发一种口服活性、优化的先导化合物，用于治疗遗忘性轻度认知障碍（aMCI）。所提出的疗法基于这样的观察：aMCI 中的记忆丧失是正常衰老和阿尔茨海默病 (AD) 之间的边界状况，与海马 CA3/齿状回 (DG) 区域的过度活动有关。减少过度活动或使其正常化有望改善这些患者的记忆力。在这种情况的动物模型中进行的临床前研究表明，选择性 GABAA β5 受体激动剂是改善记忆的有效治疗剂，其中老年大鼠的海马 CAS 神经元在记忆丧失中过度活跃。我们已经鉴定了几种对 GABAA β5 受体具有选择性的不同化学系列。这些系列中的化合物最初是由大型制药公司开发的，旨在优化反向激动剂活性，从而提高认知能力。这种方法在临床上效果不佳；事实上，支持我们拟议工作的科学预测这种方法将会失败。这些化学系列仍然具有类似药物的特性，为选择性α5受体激动剂的优化提供了起点。根据具体目标，我们将在药物化学项目中使用已建立的体外测定法来优化含有 GABAA β5 亚基受体的选择性和激动剂功效，并进行早期 ADME 和毒理学工作以确定对动物给药的适用性。然后将在衰老过程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，使用多种示踪剂和液相色谱结合串联质谱检测（LC/MS/MS）来确定体内受体占据情况，以验证目标 GABAA β5 受体的参与，以及在行为有效的剂量下对该受体亚型的选择性。在项目的最后阶段，我们将完成向 FDA 备案的先导 GABAA β5 受体激动剂的所有材料，包括药代动力学和毒理学、良好生产规范 (GMP) 合成和配方。

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.