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

摘要 阿尔茨海默病（AD）是痴呆症的最常见原因，也是老年人死亡的主要原因之一。 美国的AD是目前没有疾病修饰疗法的唯一主要死亡原因。 available.神经炎症在AD发病机制中起主要作用。环氧二十烷信号是一个关键 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（Epoxyeicosatrienoic Acids，EEA）是细胞色素P450的花生四烯酸代谢产物 具有强效抗炎活性环氧合酶。在我们的初步研究中，我们证明， sEH的药理学抑制可以减弱神经炎症，增强斑块病理学的减少， 最终逆转AD临床前模型中的空间学习和记忆缺陷。尽管一些sEH抑制剂 虽然已经报道了sEHI，但是它们都没有针对CNS应用进行优化。血脑屏障（BBB）是 CNS药物开发的主要障碍。利用高通量虚拟筛选和药物筛选技术， 通过化学优化，我们开发了EHI-16作为高度有效的、口服可利用的和脑可渗透的sEHI。 此外，EHI-16在原代星形胶质细胞和体内均减少LPS诱导的神经炎症。在这 项目，我们将进一步优化EHI-16，开发用于AD治疗的抗炎疗法。为此我们 组建了一个积极性高、经验丰富、专业知识互补的团队。王博士是一位 小分子药物发现和ADMET分析。郑博士是AD病理生理学和小鼠 建模我们的专业知识、非常有希望的初步数据和经过验证的合作记录将确保 项目的成功。在目标1中，我们将开发有效的、口服的和CNS可穿透的sEHI。 在目标2中，我们将确定sEHI与体内疗效的药代动力学-药效学关系 在AD小鼠模型中减轻神经炎症和改善认知障碍。在目标3中，我们 确定sEHI在大鼠和犬中的毒性和PK特征，并进行IND使能研究。成功 该项目的完成将为治疗和预防AD开辟一条新的途径，并将推动我们的 AD多种机制的科学知识。

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.