Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease

摘要 阿尔茨海默病(AD)是痴呆症最常见的原因，也是#年导致死亡的主要原因之一 美国。AD是目前尚无治疗方法的唯一主要致死原因 可用。神经炎症在AD的发病机制中起重要作用。环氧二十烷类信号是一个关键 中枢神经系统(CNS)细胞间通讯的整合者，协调细胞反应 不同的细胞类型。环氧二十碳三烯酸(EETs)是细胞色素P450的花生四烯酸代谢产物 具有强大抗炎活性的环氧合酶。在我们的初步研究中，我们证明了 SEH的药理抑制作用可减轻神经炎症，促进斑块病理减轻。 最终逆转AD临床前模型的空间学习和记忆缺陷。尽管一些sEH抑制剂 (SEHI)已有报道，但没有一种针对CNS应用进行了优化。血脑屏障是 中枢神经系统药物开发的主要障碍。利用高通量虚拟筛选和药物 化学优化，我们开发了EHI-16作为一种高效、口服和脑渗透的sEHI-16。 此外，EHI-16还可减少原代星形胶质细胞和体内由内毒素引起的神经炎症。在这 项目，我们将进一步优化EHI-16，开发治疗AD的抗炎疗法。为此，我们 组建了一支干劲十足、经验丰富、专业知识互补的团队。王博士是治疗癌症的专家 小分子药物发现和ADMET图谱。郑博士是AD病理生理学和小鼠研究的先驱 模特儿。我们的专业知识、极具前景的初步数据以及经过验证的协作记录将确保 拟议项目的成功。在目标1中，我们将开发有效的、口服的和中枢神经系统穿透的sEHIs。 在目标2中，我们将确定sEHIs的药代动力学-药效学关系和体内疗效。 在减轻阿尔茨海默病模型小鼠的神经炎症和改善认知功能障碍方面。在《目标3》中，我们将 确定sEHIs对大鼠和狗的毒性和PK谱，并进行IND使能研究。成功者 该项目的完成将为治疗和预防AD开辟一条新的途径，并将促进我们的 对阿尔茨海默病多种发病机制的科学认识。

ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia and one of the leading causes of death in the United States. AD is the only leading cause of death for which no disease-modifying therapy is currently available. Neuroinflammation plays a major role in AD pathogenesis. Epoxyeicosanoid signaling is a key integrator of cell-cell communication in the central nervous system (CNS), coordinating cellular responses across different cell types. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450 epoxygenase that have potent anti-inflammatory activity. In our preliminary study, we demonstrated that pharmacological inhibition of sEH can attenuate neuroinflammation, enhance reduction of plaque pathology, and eventually reverse spatial learning and memory deficits in preclinical models of AD. Although some sEH inhibitors (sEHIs) have been reported, none of them are optimized for CNS applications. Blood brain barrier (BBB) is the main hurdle for CNS drug development. Taking advantage of high throughput virtual screening and medicinal chemistry optimization, we developed EHI-16 as a highly potent, orally available and brain permeable sEHI. Additionally, EHI-16 reduces LPS-induced neuroinflammation in both primary astrocytes and in vivo. In this project, we will further optimize EHI-16 to develop anti-inflammation therapy for AD treatment. To this end, we assembled a highly motivated and experienced team with complementary expertise. Dr. Wang is an expert on small molecule drug discovery and ADMET profiling. Dr. Zheng is a pioneer on AD pathophysiology and mouse modeling. Our expertise, highly promising preliminary data, and proven collaboration track-record will ensure the success of the proposed project. In Aim 1, we will develop potent, orally available, and CNS-penetrable sEHIs. In Aim 2, we will determine the pharmacokinetics-pharmacodynamics relationship of sEHIs and in vivo efficacy in attenuating neuroinflammation and improving cognitive impairment in AD mouse models. In Aim 3, we will determine the toxicity and PK profile of sEHIs in rats and dogs and perform IND-enabling studies. The successful accomplishment of this project will open a new avenue for treating and preventing AD and will advance our scientific knowledge of multiple mechanisms of AD.