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

开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂

基本信息

批准号：
10261446
负责人：
Jin Wang
金额：
$ 208.99万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261446
关键词：
Acids Acute Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amides Amyloid beta-Protein Animals Anti-Inflammatory Agents Arachidonic Acids Astrocytes Attenuated Behavioral Binding Binding Proteins Biochemical Biological Assay Biological Availability Blood - brain barrier anatomy Brain Brain Diseases Canis familiaris Cause of Death Cell Communication Cells Central Nervous System Agents Cerebral Ischemia Clinical Collaborations Crystallization Cytochrome P450 Data Dementia Disease Disease Progression Docking Dose Drug Kinetics Ensure Enzymes Epoxide hydrolase Equilibrium Functional disorder Gene Deletion Half-Life Impaired cognition In Vitro Inflammation Inflammation Mediators Inflammatory Response Innate Immune Response Knowledge Lead Learning Legal patent Maximum Tolerated Dose Memory impairment Microglia Modeling Molecular Mus Neuraxis Neuroglia Oral Parkinsonian Disorders Pathogenesis Pathology Pattern recognition receptor Penetration Permeability Pharmaceutical Chemistry Pharmacodynamics Pharmacology Plasma Play Pre-Clinical Model Property Rattus Reporting Risk Roentgen Rays Role Safety Seizures Severity of illness Signal Transduction Structure Testing Toxic effect Toxicology Traumatic Brain Injury United States Urea Work X-Ray Crystallography base benzimidazole cell type chemoproteomics design drug development drug discovery experience improved in vivo inhibitor/antagonist mouse model neuroinflammation neurovascular unit novel pharmacophore pre-clinical prevent protein aggregation response scale up small molecule success tau Proteins virtual screening

项目摘要

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.

抽象的阿尔茨海默病（AD）是痴呆症最常见的原因，也是导致死亡的主要原因之一 AD 是目前尚无疾病缓解疗法的唯一主要原因。神经炎症在 AD 发病机制中发挥着重要作用。中枢神经系统 (CNS) 中细胞间通讯的整合者，协调细胞反应不同细胞类型的环氧二十碳三烯酸 (EET) 是细胞色素 P450 的花生四烯酸代谢物。在我们的初步研究中，我们证明了具有有效抗炎活性的环氧化酶。 sEH 的药理学抑制可以减轻神经炎症，增强斑块病理的减少，并且尽管一些 sEH 抑制剂最终逆转了 AD 临床前模型中的空间学习和记忆缺陷。 (sEHI) 已被报道，但它们都没有针对 CNS 应用进行优化。利用高通量虚拟筛选和药物开发的主要障碍。经过化学优化，我们开发了 EHI-16 作为一种高效、口服且脑可渗透的 sEHI。此外，EHI-16 LPS 在原代星形胶质细胞和体内均诱导神经炎症。项目中，我们将进一步优化EHI-16来开发用于AD治疗的抗炎疗法。王博士组建了一支积极进取、经验丰富、专业知识互补的团队。郑博士是 AD 病理生理学和小鼠研究的先驱。我们的专业知识、极具前景的初步数据以及经过验证的合作记录将确保在目标 1 中，我们将开发有效的、口服的、中枢神经系统可渗透的 sEHI。在目标 2 中，我们将确定 sEHI 的药代动力学-药效学关系和体内功效在目标 3 中，我们将减轻 AD 小鼠模型的神经炎症并改善认知障碍。确定 sEHI 在大鼠和狗中的毒性和 PK 特征，并成功开展 IND 启用研究。该项目的完成将为治疗和预防 AD 开辟一条新途径，并将推进我们的研究 AD 多种机制的科学知识。