Development of small molecule activators of glutamate transporter EAAT2 for treatment of Alzheimer's disease

项目摘要 谷氨酸转运体EAAT2在胞外动态平衡调节中的重要作用 谷氨酸水平。EAAT2在认知记忆功能中也起着至关重要的作用。然而，损失 EAAT2蛋白和功能在阿尔茨海默病(AD)患者中很常见，是早期的 疾病病理学中的事件。我们最近发现，通过一种新的方法恢复了EAAT2蛋白的功能 脑穿透性小分子，我们之前发现它能够增加EAAT2 通过翻译激活表达，显著改善认知功能并恢复 阿尔茨海默病应用程序鼠标模型的突触完整性。我们积极优化了这一系列化合物，并 确定了一些有效的口服生物可用化合物。在此应用程序中，我们寻求支持以 将该项目从优化的化合物推进到“临床候选药物”。在第一年，我们将专注于 通过一系列体外实验从一组10个完全优化的化合物中鉴定铅分子 以及体内疗效、选择性和安全性评价。在2-3年级，我们将重点评估 在APPSw、Ind小鼠和RTG(TauP301L)4510小鼠两种AD模型中的铅分子，并鉴定 化合物作为临床候选药物。

Project Summary Glutamate transporter EAAT2 plays a critical role in the homeostatic regulation of extracellular glutamate levels. EAAT2 also plays an essential role in cognitive memory functions. However, loss of EAAT2 protein and function are commonly found in Alzheimer’s Disease (AD) patients and are an early event in disease pathology. We recently discovered that restoration of EAAT2 protein function by a novel brain-penetrant small molecule, which we previously identified as capable of increasing EAAT2 expression through translational activation, significantly improved cognitive functions and restored synaptic integrity in an APP mouse model of AD. We have actively optimized this compound series and identified a number of potent and orally bioavailable compounds. In this application, we seek support to move the project forward from optimized compounds to "a clinical candidate". In Year 1, we will focus on identifying the lead molecule from a group of ten fully optimized compounds through a series of in vitro and in vivo efficacy, selectivity, and safety evaluations. In Years 2-3, we will focus on evaluation of the lead molecule in two AD models, APPSw,Ind mice and rTg(tauP301L)4510 mice, and identify the compound as the clinical candidate.