Discovery/Development of GABA-A α5 Positive Allosteric Modulators for Treatment of MCI due to AD

该UH2申请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 α 5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 α 5 PAM程序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。 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表明， 支持减少海马过度活跃可能是治疗性的概念， 有利于从啮齿类动物与年龄相关的记忆障碍的研究， 遗忘型MCI患者的临床研究， 内侧颞叶/海马和记忆性能已经被 通过低剂量左乙拉西坦治疗证实， 过度活跃GABA-A α 5受体在海马的强定位与 其控制紧张性抑制的作用使GABA-A α 5 PAM非常适合于减少 AD导致MCI的海马活动过度。 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 α 5受体PAM是有效的， 改善记忆的治疗剂。通过不断的药物化学努力， AgeneBio的GABA-A α 5 PAM项目正处于先导化合物优化的探索阶段。的 筛选树定义明确，所有测定均已到位，化合物已进展 通过筛选树。有效和选择性的GABA-A α 5 PAMS，具有良好的体外 ADME特性和体内受体占有率已被确定。此外，本发明还 几种化合物在年龄的放射臂迷宫任务中显示出体内功效， 记忆力受损的老鼠。改善血脑屏障渗透和 口服生物利用度是必需的，以便宣布一种先导化合物可以用于 发展

The overall objective of this UH2 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. Recent preclinical and clinical studies using the atypical antiepileptic levetiracetam have supported the concept that reduction of hippocampal overactivity may be therapeutically beneficial. 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. Through ongoing medicinal chemistry efforts, AgeneBio’s GABA-A α5 PAM program is at a Discovery stage of lead optimization. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. Potent and selective GABA-A α5 PAMS with good in vitro ADME properties and in vivo receptor occupancy have been identified. Additionally, several compounds demonstrate efficacy in vivo in a radial arm maze task in age- associated memory impaired rats. Improvements in blood brain barrier penetration and oral bioavailability are required in order to declare a lead compound ready for Development.