Discovery/Development of GABA-A ñ5 Positive Allosteric Modulators for Treatment of MCI due to AD

UH2应用的总体目标是开发一种有效的、选择性的和口服活性的α-APAM阳性变构调节剂，用于治疗阿尔茨海默病(AD)的早期症状阶段。GABA-Aα5阳性变构调节剂的靶点是在内侧颞叶的海马网中出现异常的神经过度活动，在这种神经退行性疾病中，早期细胞变性发生在那里。阿尔茨海默病的这一阶段通常被称为阿尔茨海默病引起的轻度认知障碍(MCI因AD)，因为患者进展到临床诊断痴呆症的症状标准。目前还没有批准的治疗方法来治疗这一适应症，这使得这一领域的需求极高，尚未得到满足。临床前AD模型有力地支持了控制多动是有效的。Agene Bio的GABA-Aα5 PAM计划代表了一种新的方法，可以解决这一患者群体中过度的海马体活动，进一步发展的风险很高。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了减少海马区过度活动有益的概念。同样的治疗方法在多种淀粉样蛋白和tau病理的临床前AD模型中都显示出了疗效。GABA-Aα5受体在海马区的强烈定位，再加上其控制紧张性抑制的作用，使得α5 PAM非常适合于减少AD早期海马区的过度活动。通过持续的药物化学努力，Agene Bio的GABA-Aα5 PAM计划正在进行 线索优化的发现阶段。筛选树定义良好，所有分析都已到位，化合物已通过筛选树。高效和选择性的α-A GABA-5PAMS具有良好的体外ADME性质和体内受体占有率。此外，几种化合物在与年龄相关的记忆受损大鼠的放射臂迷宫任务中显示了有效性。需要改善血脑屏障穿透性和口服生物利用度，才能宣布一种领先化合物已准备好开发。

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 Alzheimer’s Disease (AD) in its earliest symptomatic stages. The target of the GABA-A α5 Positive Allosteric Modulator (PAM) is the occurrence of aberrant neural overactivity in the hippocampal network of the medial temporal lobe where early cellular degeneration occurs in this neurodegenerative disease. This phase of Alzheimer’s is often referred to as Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD), as patients progress to the symptomatic criteria for a clinical diagnosis of dementia. 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 that control of hyperactivity is efficacious. 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 further progression. Recent preclinical and clinical studies using the atypical antiepileptic levetiracetam have supported the concept that reduction of hippocampal overactivity is beneficial. That same treatment has shown efficacy in multiple preclinical AD models of both amyloid and tau pathology. 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 early AD. 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.