Structurally Diverse GABA-A a5 Positive Allosteric Modulators for Treatment of MCI due to AD

结构多样化的 GABA-A a5 正变构调节剂用于治疗 AD 引起的 MCI

• 批准号: 10248568
• 负责人: Sharon Rosenzweig-Lipson
• 金额: $ 62.57万
• 依托单位: AGENEBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248568
• 关键词: ABCB1 gene; Address; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease model; Antiepileptic Agents; Area; Binding Proteins; Biological Assay; Biological Availability; Caregivers; Chemicals; Clinical; Clinical Research; Coupled; Development; Dose; Funding; Goals; Grant; Healthcare Systems; Hippocampus (Brain); Human; Impairment; Lead; Levetiracetam; Medial; Memory; Memory Loss; Modeling; Neurons; Oral; Oral Administration; Pathology; Patients; Performance; Pharmaceutical Chemistry; Phase; Plasma Proteins; Radial; Rattus; Research; Resources; Risk; Rodent; Role; Series; Small Business Innovation Research Grant; Solubility; Structure; Temporal Lobe; Therapeutic; Therapeutic Agents; Trees; Work; aqueous; arm; brain dysfunction; dementia risk; design; gamma-Aminobutyric Acid; high risk; improved; in vivo; lead series; mild cognitive impairment; neuronal circuitry; novel; novel strategies; patient population; positive allosteric modulator; pre-clinical; preclinical study; programs; receptor; scaffold; screening; therapeutic biomarker; therapeutically effective

The overall objective of this SBIR 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. The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent preclinical and clinical studies using the atypical antiepileptic levetiracetam. 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. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. The program lead series (funded by the Blueprint Neurotherapeutics Network) has potent and selective GABA-A α5 PAM compounds with good in vivo efficacy in an age-impaired rat. However, should the lead series falter at any point for reasons independent of mechanism of action, it is critical that a second series be identified that could rapidly be evaluated to mitigate the overall program risk. The purpose of this SBIR grant is to expand the structurally distinct, non-BZD second series scaffold to identify potent and selective GABA-A α5 compounds for the treatment of MCI due to AD.

这项SBIR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 GABA-Aα5阳性变构调节剂治疗轻度认知障碍 由于阿尔茨海默病(由于阿尔茨海默病引起的MCI)。目前还没有批准的治疗方法来治疗 这一迹象表明，这是一个极高的未得到满足的需求领域。得到了……的大力支持 临床前AD模型和人类患者，特别是在AD的早期阶段，神经元 海马体中的回路变得过度活跃，导致神经元病理和 大脑功能障碍。Agene Bio的GABA-Aα5 PAM计划代表了一种新的方法 解决这一痴呆症高危人群中海马体过度活动的问题。 减少海马区过度活动对治疗有益的概念得到了支持 通过最近的临床前和临床研究使用非典型的抗癫痫药物左乙拉西坦。测距 从啮齿动物年龄相关性记忆障碍的研究到患者的临床研究 遗忘性MCI对内侧颞叶/海马区关键回路的有益影响 以及对记忆性能的影响已经通过低剂量的 减少海马区过度活动的左乙拉西坦。大鼠海马区的强烈定位 GABA-Aα5受体及其控制紧张性抑制作用使GABA-Aα5 PAM 非常适合于减少AD引起的MCI中海马区的过度活动。 显示海马区的增龄性记忆丧失大鼠的临床前研究 过度活跃表明选择性GABA-Aα5受体PAM是有效的治疗 改善记忆力的药剂。筛选树定义良好，所有分析均已到位，以及 化合物已经通过了筛选树。 该计划的主导系列(由蓝图神经治疗网络资助)具有强大的 选择性GABA-Aα5-PAM化合物在衰老大鼠体内具有良好的疗效。 然而，如果铅系列在任何时候由于独立于机制的原因而摇摇欲坠 行动，关键是确定第二个系列，可以迅速评估以缓解 整个项目的风险。这项SBIR赠款的目的是扩大结构独特的、 非BZD第二系列支架用于鉴定有效和选择性的GABA-Aα5化合物 阿尔茨海默病所致轻度认知功能障碍的治疗。