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.

这项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（Positive Allosteric Modulator， PAM）的作用靶点是这种神经退行性疾病中发生早期细胞变性的内侧颞叶海马网络异常神经过度活动的发生。随着患者发展到痴呆临床诊断的症状标准，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由于AD）。目前还没有批准的治疗这种适应症的药物，这使得这一领域的需求非常高。临床前AD模型强有力地支持了多动症的控制是有效的。AgeneBio的GABA-A α5 PAM项目代表了一种新的方法，可以解决这种高风险进一步进展的患者群体中过量的海马活动。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了减少海马过度活动是有益的这一概念。同样的治疗在淀粉样蛋白和tau蛋白病理的多种临床前AD模型中显示出疗效。GABA-A α5受体在海马的强定位及其控制强张性抑制的作用使得GABA-A α5 PAMs非常适合用于减少早期AD的海马过度活动。通过持续的药物化学努力，AgeneBio公司的GABA-A α5 PAM项目正在取得进展