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

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)之间的一种边缘状态，这种记忆丧失是 与海马区CA3/齿状回(DG)的过度活动有关。减少过剩 活动或将其正常化，有望改善这些患者的记忆力。一种动物的临床前研究 在这种情况下，记忆丧失的老年大鼠海马区CAS神经元过度活跃， 表明选择性的gabaaa5受体激动剂是改善 记忆。我们已经确定了几个不同的化学系列，它们对GABAA a5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，以优化 以改善认知为目标的反向激动剂活动。这种方法在以下方面并不有效 事实上，支持我们提议的工作的科学将预测这种方法将失败。仍然 这些化学系列具有类似药物的性质，为选择性a5的优化提供了一个起点。 受体激动剂。在特定的目标下，我们将在药物化学中使用已建立的体外分析 优化含有受体和传导的GABAA a5亚基的选择性和激动剂效果的计划 早期的ADME和毒理学工作是为了确定给动物服用的适宜性。体内研究将 然后在老年记忆丧失的动物模型上进行实验，该模型反映了老年人观察到的许多特征 人类，尤其是MCI。通过多项研究确定受体在体内的占有率 与串联质谱检测(LC/MS/MS)联用的示踪剂也将 进行以验证目标GABAA a5受体的结合以及对该受体的选择性 亚型，剂量在行为上有效。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)合成和 GABAA a5受体激动剂配方向美国食品及药物管理局备案。 相关性(请参阅说明)：

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):