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

该SBIR申请的总体目标是开发一种有效的、选择性的和口服活性的 GABA-A α5阳性变构调节剂治疗轻度认知功能障碍 阿尔茨海默氏病（AD导致的MCI）目前还没有批准的治疗方法， 这一迹象表明，这是一个需求极高的领域。得到了来自 临床前AD模型和人类患者，特别是在AD的早期阶段， 海马体中的回路变得过度活跃，导致神经元病理学， 脑功能障碍AgeneBio的GABA-A α5 PAM项目代表了一种新的方法， 解决了痴呆症高危患者群体中海马体的过度活动。 这一概念，减少海马过度活跃是有益的治疗支持 通过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。测距 从啮齿类动物与年龄相关的记忆障碍研究到患者的临床研究， 对于遗忘型MCI，对内侧颞叶/海马中的关键回路产生有益影响 和记忆性能的影响已经通过低剂量的 左乙拉西坦可以降低海马过度活跃。强海马定位 GABA-A α5受体偶联其控制紧张性抑制的作用使GABA-A α5 PAM 非常适合于减少AD引起的MCI中的过度海马活动。 在具有年龄相关性记忆丧失的大鼠中进行的临床前研究显示， 过度活性表明选择性GABA-A α5受体PAM是有效的治疗剂， 提高记忆力的药物筛选树定义明确，所有测定均已到位， 化合物已经通过筛选树前进。 该计划领导系列（由蓝图神经治疗网络资助）具有强大的， 选择性GABA-A α5 PAM化合物在年龄受损大鼠中具有良好的体内功效。 然而，如果铅系列在任何时候由于与机械无关的原因而动摇， 行动，至关重要的是，确定第二个系列，可以迅速评估，以减轻 整体方案风险。这项SBIR赠款的目的是扩大结构独特， 非BZD第二系列支架，以鉴定用于治疗的有效和选择性GABA-A α5化合物。 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.