Structurally Diverse GABA-A a5 Positive Allosteric Modulators for Treatment of MCI due to AD

该SBIR应用的总体目标是开发一种有效的、选择性的和口服的 活性GABA-A α5阳性变构调节剂（PAM）治疗轻度 阿尔茨海默病导致的认知障碍（AD导致的MCI）。目前有 没有批准用于该适应症的治疗方法，使其成为一个极高的领域 未满足的需求有来自临床前AD模型和人类患者的强有力的支持， 特别是在AD的早期阶段，海马体中的神经元回路变得 过度活跃导致神经元病理和脑功能障碍。AgeneBio的 GABA-A α5 PAM计划代表了一种解决过量的 海马活动在这个患者群体中处于痴呆症的高风险。概念 海马过度活跃的减少在治疗上是有益的，这一点得到了以下证据的支持： 最近使用非典型抗癫痫药物左乙拉西坦的临床前和临床研究。 从啮齿动物年龄相关记忆障碍的研究到临床 对遗忘型MCI患者的研究，对内侧关键回路的有益影响 颞叶/海马和对记忆性能的影响已经被证明， 以低剂量左乙拉西坦治疗，减少海马过度活动。的 GABA-A α5受体在海马的强定位及其在控制 紧张性抑制使GABA-A α5 PAM非常适合于减少过量的海马 由于AD而导致的MCI活动。年龄相关性记忆丧失大鼠的临床前研究 显示海马过度活跃，表明选择性GABA-A α5受体 PAM是改善记忆的有效治疗剂。筛选树很好 定义，所有的测定都在适当的位置，化合物已经通过筛选 树该计划领导系列（由蓝图神经治疗网络资助） 有效和选择性的GABA-A α5 PAM化合物，在年龄- 受损大鼠然而，如果铅系列动摇在任何时候的原因 与作用机制无关，关键是要确定第二个系列， 可以快速评估，以减轻整体计划风险。本SBIR的目的 格兰特是扩大结构独特的，非BZD第二系列支架，以确定 有效和选择性的GABA-A α5化合物，用于治疗AD引起的MCI。

The overall objective of this SBIR application is to develop a potent, selective and orally active GABA-A α5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD). There are currently no approved therapeutics for this indication making this an area of extremely high unmet need. There is strong support from preclinical AD models and human patients, particularly in this early stage of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunction. AgeneBio’s GABA-A α5 PAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for dementia. The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent preclinical and clinical studies using the atypical antiepileptic levetiracetam. Ranging from research on age-associated memory impairment in rodents to clinical studies in patients with amnestic MCI, beneficial effects on key circuits in the medial temporal lobe/hippocampus and on memory performance have been demonstrated by treatment at low doses of levetiracetam that reduce hippocampal overactivity. The strong hippocampal localization of GABA-A α5 receptors coupled with its role to control tonic inhibition make GABA-A α5 PAMs well suited to reduce the excess hippocampal activity in MCI due to AD. Preclinical studies in rats with age-associated memory loss which show hippocampal overactivity demonstrate that selective GABA-A α5 receptor PAMs are effective therapeutic agents to improve memory. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. The program lead series (funded by the Blueprint Neurotherapeutics Network) has potent and selective GABA-A α5 PAM compounds with good in vivo efficacy in an age- impaired rat. However, should the lead series falter at any point for reasons independent of mechanism of action, it is critical that a second series be identified that could rapidly be evaluated to mitigate the overall program risk. The purpose of this SBIR grant is to expand the structurally distinct, non-BZD second series scaffold to identify potent and selective GABA-A α5 compounds for the treatment of MCI due to AD.