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

这种UH2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γ-氨基丁酸-Aα5阳性变构调节剂治疗轻症 阿尔茨海默病引起的认知障碍(阿尔茨海默病引起的MCI)。目前有 没有批准的治疗方法使这一适应症成为一个极高的领域 未得到满足的需求。这得到了临床前AD模型和人类患者的大力支持， 特别是在阿尔茨海默病的早期阶段，海马区的神经元回路成为 过度活跃导致神经元病理和脑功能障碍。Agene Bio的 GABA-Aα5 PAM计划代表了一种解决过剩问题的新方法 痴呆高危人群中的海马体活动。 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 支持减少海马区过度活动的概念可能是治疗上的 有益的。从对啮齿动物年龄相关性记忆障碍的研究到 遗忘型MCI患者的临床研究，对大脑关键回路的有益影响 内侧颞叶/海马区和记忆能力 低剂量左乙拉西坦治疗可减少海马区 过度活跃。γ-氨基丁酸-A-α_5受体在海马区的强定位 其控制紧张性抑制的作用使GABA-Aα5 PAM非常适合于降低 阿尔茨海默病所致的MCI患者的海马区过度活动。 显示海马区的增龄性记忆丧失大鼠的临床前研究 过度活性证明选择性α-A受体PAM有效 改善记忆力的治疗剂。通过持续的药物化学努力， Agene Bio的GABA-Aα5 PAM计划正处于领先优化的发现阶段。这个 筛选树定义良好，所有分析都已到位，化合物已取得进展 穿过屏蔽树。高效、选择性的GABA-Aα5 PAMS体外良好 ADME的性质和体内受体的占有率已经确定。另外， 几种化合物在年龄段的放射臂迷宫任务中显示出了体内的有效性-- 相关记忆受损的大鼠。改善血脑屏障穿透性和 需要口服生物利用度才能宣布一种先导化合物已准备好用于 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.