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: 10189063
• 负责人: Sharon Rosenzweig-Lipson
• 金额: $ 124.91万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189063
• 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; Treatment Efficacy; 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

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.

该 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药物 GABA-A α5 正变构调节剂 (PAM) 用于治疗轻度认知障碍 由于阿尔茨海默病（AD 引起的 MCI）。目前尚无批准的治疗方法 这一迹象表明该领域的需求未得到满足的程度极高。有来自以下方面的大力支持 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，导致神经元病理学和 脑功能障碍。 AgeneBio 的 GABA-A α5 PAM 项目代表了一种新颖的方法 解决痴呆症高风险患者群体中过度的海马活动问题。 支持减少海马过度活动对治疗有益的概念 最近使用非典型抗癫痫药左乙拉西坦进行的临床前和临床研究。测距 从啮齿类动物与年龄相关的记忆障碍研究到患者临床研究 遗忘性MCI，对内侧颞叶/海马的关键回路产生有益影响 低剂量的治疗已证明对记忆力的影响 左乙拉西坦可减少海马过度活动。强烈的海马定位 GABA-A α5 受体及其控制强直抑制的作用使得 GABA-A α5 PAM 非常适合减少 AD 引起的 MCI 中过度的海马活动。 对与年龄相关的记忆丧失的大鼠进行的临床前研究表明，海马 过度活性证明选择性 GABA-A α5 受体 PAM 是有效的治疗药物 改善记忆力的药剂。筛选树已明确定义，所有测定均已到位，并且 化合物已通过筛选树。 该项目主导系列（由 Blueprint Neurotherapeutics Network 资助）具有有效且 选择性 GABA-A α5 PAM 化合物在老年大鼠体内具有良好的体内功效。 然而，如果引线系列在任何时候由于独立于机制的原因而动摇， 行动，至关重要的是确定第二个系列，可以快速评估以减轻影响 总体计划风险。 SBIR 拨款的目的是扩大结构上独特的、 非 BZD 第二系列支架，用于鉴定有效且选择性的 GABA-A α5 化合物 治疗 AD 引起的 MCI。