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

基本信息

批准号：
10290945
负责人：
Sharon Rosenzweig-Lipson
金额：
$ 23.54万
依托单位：
AGENEBIO, INC.
依托单位国家：
美国
项目类别：
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/10290945
关键词：
Address Age Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Antiepileptic Agents Area Biological Assay Caregivers Chemicals Clinical Clinical Research Coupled Dose Funding Goals Grant Healthcare Systems Hippocampus (Brain)Human Impairment Levetiracetam Medial Memory Memory Loss Neurons Oral Pathology Patients Performance Rattus Research Risk Rodent Role Series Small Business Innovation Research Grant Structure Temporal Lobe Therapeutic Therapeutic Agents Trees brain dysfunction dementia risk 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

项目摘要

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、口服的活性 GABA-A α5 正变构调节剂 (PAM) 用于治疗轻度阿尔茨海默病引起的认知障碍（AD 引起的 MCI）目前有。目前尚无针对该适应症的批准治疗方法，这使得该领域的风险极高未满足的需求得到了临床前 AD 模型和人类患者的大力支持，特别是在 AD 的早期阶段，海马体中的神经回路变得过度活跃会导致神经元病理学和脑功能障碍。 GABA-A α5 PAM 计划代表了一种解决过量问题的新方法痴呆症高危人群的海马活动这一概念。减少海马过度活动的治疗是有益的，这一点得到以下支持最近使用非典型抗癫痫左乙拉西坦进行的临床前和临床研究。从啮齿类动物年龄相关记忆障碍的研究到临床针对遗忘性 MCI 患者的研究，对内侧关键回路产生有益影响颞叶/海马体和记忆表现已被证明低剂量左乙拉西坦治疗可减少海马过度活动。 GABA-A α5 受体在海马的强烈定位及其控制作用强直抑制使 GABA-A α5 PAM 非常适合减少多余的海马 AD 引起的 MCI 活性在患有与年龄相关的记忆丧失的大鼠中进行的临床前研究。显示海马过度活跃表明选择性 GABA-A α5 受体 PAM 是改善记忆的有效治疗剂。筛选树很好。已定义，所有测定均已到位，并且化合物已通过筛选项目主导系列（由蓝图神经治疗网络资助）有有效且选择性的 GABA-A α5 PAM 化合物，在年龄组中具有良好的体内功效然而，如果铅系列因某种原因而在任何时候动摇。独立于作用机制，确定第二个系列至关重要可以快速评估以减轻总体计划风险。赠款旨在扩展结构独特的非 BZD 第二系列支架，以确定有效且选择性的 GABA-A α5 化合物，用于治疗 AD 引起的 MCI。