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

描述（由申请人提供）：本次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）。aMCI是介于正常衰老和阿尔茨海默病（AD）之间的一种边缘状态，aMCI患者的记忆丧失与海马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。老年记忆丧失大鼠海马CAS神经元过度活跃的动物模型临床前研究表明，选择性GABAA α5受体激动剂是改善记忆的有效药物。我们已经确定了几种不同的化学系列对GABAA α5受体具有选择性。这些系列中的化合物最初是由大型制药公司开发的，目的是优化逆激动剂的活性，以改善认知。这种方法在临床上并不有效；事实上，支持我们提议的工作的科学预测，这种方法将会失败。然而，这些化学系列具有类似药物的性质，为选择性α5受体激动剂的优化提供了一个起点。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试验来优化GABAA α5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，以确定给药的动物适用性。随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类中观察到的许多特征，特别是aMCI。使用液相色谱耦合串联质谱检测（LC/MS/MS）的多种示踪剂确定体内受体占用的伴随研究也将进行，以验证目标GABAA α5受体的参与，以及该受体亚型的选择性，在行为有效的剂量下。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，良好生产规范（GMP）合成和向FDA提交GABAA α5受体激动剂先导剂的配方。

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 α5 receptor agonists are effective therapeutic agents to improve memory. We have identified several different chemical series that are selective for GABAA α5 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 α5 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 α5 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 α5 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 α5 receptor agonist filing with the FDA.