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

描述(申请人提供)：这项U01申请的总体目标是开发一种口服活性的、优化的铅化合物，用于治疗遗忘性轻度认知障碍(AMCI)。建议的治疗是基于以下观察结果：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，其记忆丧失与海马区CA3/齿状回(DG)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。在老年记忆丧失大鼠海马区CAS神经元过度活跃的动物模型上进行的临床前研究表明，选择性GABAA？5受体激动剂是改善记忆的有效治疗药物。我们已经确定了几个不同的化学系列，它们对GABAA？5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，目的是优化反向激动剂的活性，目的是改善认知。这种方法在临床上并不有效；事实上，支持我们拟议工作的科学将预测这种方法将失败。尽管如此，这些化学系列具有类似药物的特性，为优化选择性受体激动剂提供了一个起点。在特定的目标下，我们将在药物化学项目中使用建立的体外分析来优化含有受体的GABAA？5亚基的选择性和激动剂效果，并进行早期的ADME和毒理学工作，以确定给动物使用的适宜性。然后，将在衰老中进行记忆丧失的动物模型的活体研究，该模型反映了在老年人中观察到的许多特征，特别是MCI。同时，还将进行一系列研究，以确定体内受体的占有率，该研究使用多种示踪剂，结合高效液相色谱和串联质谱学检测(LC/MS/MS)，以验证目标GABAA？5受体的结合以及对该受体亚型的选择性，剂量是行为有效的。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、良好制造规范(GMP)的合成以及向FDA提交的GABAA？5受体激动剂的配方。

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 ?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.