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: 9766835
• 负责人: Sharon Rosenzweig-Lipson
• 金额: $ 13.49万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766835
• 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; Blood - brain barrier anatomy; Chemicals; Clinical; Clinical Research; Coupled; Dementia; Development; Disease Progression; Goals; Hippocampus (Brain); Hyperactive behavior; In Vitro; Lead; Levetiracetam; Medial; Neurodegenerative Disorders; Neurons; Oral; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Phase; Production; Property; Radial; Rattus; Role; Temporal Lobe; Therapeutic; Trees; arm; 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.

UH 2申请的总体目标是开发一种有效、选择性和口服活性的GABA-A α5阳性变构调节剂（PAM），用于治疗早期症状阶段的阿尔茨海默病（AD）。GABA-A α5阳性变构调节剂（PAM）的靶点是内侧颞叶海马网络中异常神经过度活动的发生，在这种神经退行性疾病中，内侧颞叶海马网络中发生早期细胞变性。阿尔茨海默病的这个阶段通常被称为阿尔茨海默病所致的轻度认知障碍（AD所致的MCI），因为患者进展到痴呆临床诊断的症状标准。目前尚无针对该适应症的获批治疗药物，这使得该领域的需求极高。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项目代表了一种新的方法，可以解决这种具有进一步进展高风险的患者人群中海马体过度活动的问题。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过度活动有益的概念。相同的治疗在淀粉样蛋白和tau病理学的多个临床前AD模型中显示出疗效。GABA-A α5受体的强海马定位及其控制紧张性抑制的作用使GABA-A α5 PAM非常适合于降低早期AD的过度海马活动。通过持续的药物化学努力，AgeneBio的GABA-A α5 PAM项目处于 潜在客户优化的发现阶段。筛选树定义明确，所有试验均已到位，化合物已通过筛选树。已鉴定出具有良好体外ADME特性和体内受体占有率的有效和选择性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和口服生物利用度，以宣布准备开发的先导化合物。