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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：
10663178
负责人：
Jin Wang
金额：
$ 102.37万
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/10663178
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 Central Nervous System Agents Cerebral Ischemia Clinical Collaborations Cytochrome P450 Cytoprotection 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 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 benzimidazole cell type chemoproteomics design drug development drug discovery efficacy evaluation experience improved in vivo inhibitor mouse model neuroinflammation neuroprotection neurovascular unit novel pharmacologic 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.

摘要