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

发现/开发 GABA-A –5 正变构调节剂，用于治疗 AD 引起的 MCI

• 批准号: 10009475
• 负责人: Sharon Rosenzweig-Lipson
• 金额: --
• 依托单位: AGENEBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009475
• 关键词: Address; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Antiepileptic Agents; Area; Automobile Driving; Biological Assay; Biological Availability; Chemicals; Clinical; Clinical Research; Coupled; Dementia; Development; Disease Progression; Goals; Hippocampus (Brain); Hyperactivity; In Vitro; Lead; Levetiracetam; Medial; Neurodegenerative Disorders; Neurons; Oral; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Phase; Production; Property; Radial; Rattus; Role; Temporal Lobe; Therapeutic; Trees; arm; blood-brain barrier penetration; clinical Diagnosis; gamma-Aminobutyric Acid; high risk; in vivo; lead optimization; mild cognitive impairment; novel; novel strategies; patient population; positive allosteric modulator; pre-clinical; preclinical study; programs; receptor; relating to nervous system; screening; tau Proteins; therapeutic biomarker

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.

UH2 应用的总体目标是开发一种有效的、选择性的、口服活性的 GABA-A α5 正变构调节剂 (PAM)，用于治疗阿尔茨海默病 (AD) 的最早症状阶段。正变构调节剂 (PAM) 是指内侧颞叶海马网络中发生异常神经过度活动，在这种神经退行性疾病的这一阶段，该区域发生早期细胞变性。通常被称为阿尔茨海默氏病引起的轻度认知障碍（AD 引起的 MCI），因为患者已达到痴呆症临床诊断的症状标准，目前尚无针对该适应症的批准治疗方法，这使得该领域成为一个极其危险的领域。临床前 AD 模型强烈支持控制多动症是有效的，AgeneBio 的 GABA-A α5 PAM 计划代表了一种解决该患者群体海马活动过度的新方法。最近使用非典型抗癫痫左乙拉西坦的临床前和临床研究支持了这样的观点，即减少海马过度活动是有益的，这种治疗在多种淀粉样蛋白和 tau 病理学临床前 AD 模型中都显示出疗效。 GABA-A α5 受体的结合及其控制强直抑制的作用，使得 GABA-A α5 PAM 非常适合减少早期海马的过度活动。 AD。通过持续的药物化学努力，AgeneBio 的 GABA-A α5 PAM 项目正在取得进展。 先导物优化的发现阶段已明确，所有测定均已到位，并且化合物已通过筛选树，并已鉴定出具有良好体外 ADME 特性和体内受体占据性的有效且选择性的 GABA-A α5 PAMS。此外，几种化合物在与年龄相关的记忆受损大鼠的径向臂迷宫任务中表现出体内功效，需要改善血脑屏障渗透性和口服生物利用度，才能宣布先导化合物已准备好进行开发。