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：
10032662
负责人：
Jin Wang
金额：
$ 181万
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/10032662
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.

抽象的阿尔茨海默氏病（AD）是痴呆症的最常见原因，也是死亡的主要原因之一美国。 AD是目前尚无疾病修改治疗的唯一主要死亡原因可用的。神经炎症在AD发病机理中起主要作用。环氧树脂信号传导是关键中枢神经系统（CNS）中细胞 - 细胞通信的积分器，横跨细胞反应不同的细胞类型。环氧气酸（EET）是细胞色素P450的花生四烯酸代谢产物具有潜在抗炎活性的环氧酶。在我们的初步研究中，我们证明了 SEH的药理抑制作用可以减轻神经炎症，牙菌斑病理学的减少和在AD的临床前模型中，均匀的反向空间学习和记忆定义。虽然有些SEH抑制剂（SEHIS）已有报道，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。利用高吞吐量虚拟筛查和医疗化学优化，我们开发了EHI-16作为高潜力，口服可用的和可渗透性的SEHI。此外，EHI-16可减少原代星形胶质细胞和体内LPS诱导的神经炎症。在这个项目，我们将进一步优化EHI-16，以开发用于AD治疗的抗炎疗法。为此，我们组建了一支具有完善专业知识的积极进取和经验丰富的团队。 Wang博士是专家小分子药物发现和助力分析。郑博士是AD病理生理学和小鼠的先驱造型。我们的专业知识，非常有前途的初步数据，并证明协作曲目纪录将确保拟议项目的成功。在AIM 1中，我们将开发潜力，口服和CNS可渗透的SEHIS。在AIM 2中，我们将确定Sehis和体内效率的药代动力学 - 剂量动力学关系在衰减神经炎症并改善AD小鼠模型中的认知障碍时。在AIM 3中，我们将确定Sehis在大鼠和狗中的毒性和PK谱，并进行辅助研究。成功实现该项目将为治疗和预防广告开辟新的途径，并将推动我们的 AD多种机制的科学知识。