Development of soluble epoxide hydrolase inhibitors for the treatment of Alzheimer's disease

开发用于治疗阿尔茨海默病的可溶性环氧化物水解酶抑制剂

基本信息

批准号：
10567257
负责人：
Kin Sing Stephen Lee
金额：
$ 64.99万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567257
关键词：
Acids Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient American Amyloidosis Animal Diseases Animal Model Binding Biological Biological Assay Biological Markers Blood - brain barrier anatomy Brain Cause of Death Chronic Computer Models Data Dementia Development Disease Dose Drug Kinetics Drug Targeting Enzyme Inhibition Enzymes Epoxide hydrolase Exposure to Fatty Acids Genetic Goals Impaired cognition In Vitro Inflammatory Kinetics Knock-out Lead Learning Letters Medical Methodology Modeling Modification Mus Neurodegenerative Disorders Oral Parkinson Disease Pathogenesis Pathologic Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Population Preclinical Testing Property Quality of life Rattus Reporting Research Series Structure-Activity Relationship Symptoms System Tauopathies Testing Therapeutic Time United States analog blood-brain barrier penetration candidate selection clinical candidate clinical development cognitive function design drug discovery effective therapy efficacy evaluation efficacy testing experience experimental study human old age (65+)improved in vivo inhibitor inhibitor therapy lead candidate multidisciplinary nanomolar neuroinflammation new therapeutic target novel pharmacophore physical property pre-clinical preclinical efficacy preclinical study prevent programs research and development residence therapeutic target tool vascular abnormality

项目摘要

Abstract Alzheimer’s disease affects 6 million Americans, is the 6th leading cause of death in the nation and substantially impacts patients’ quality of life with no effective cure available. As the population over the age of 65 is projected to triple by 2035, the number of Alzheimer’s disease patients is expected to increase by at least two-fold. Therefore, there is an unmet medical need to develop novel treatments to prevent and or cure Alzheimer’s disease. Recent studies indicate that soluble epoxide hydrolase (sEH) is a novel therapeutic target for Alzheimer’s disease. Although the newer sEH inhibitors have sub-nanomolar potency, they generally suffer from poor blood- brain barrier penetration and unsuitable physical properties. As a high percentage of sEH inhibition / engagement is needed to elicit significant biological activity, sEH inhibitors with high blood-brain barrier penetration and exposure are needed. Although the structure-activity relationships (SARs) of sEH inhibitors have been extensively investigated, their impact on blood-brain barrier penetration has rarely been studied and the existing clinical candidates are predicted to have poor CNS exposure. While most of the SAR studies focus on the substituents on both ends of the inhibitors, the linker of the inhibitors has rarely been explored. We will investigate how modifications of sEHI’s linker and other modifications affect its CNS drug-like properties and CNS exposure. We will then systematically incorporate the optimized modifications to further improve sEHI’s drug-like properties and CNS exposure. Aim 1 of this project will apply a novel design-test-learn strategy to guide the design of the novel sEHIs using our in- house assays to screen sEHIs potency, binding kinetics and in vitro pharmacokinetic parameters. The top candidates will be screened for their PK properties and CNS exposure using our established low dose oral cassette dosing methodology. We will then further determine the detailed pharmacokinetic properties and CNS exposure parameters of the selected candidates. As the program progresses, we will our observations for further optimization. The optimized candidates will be selected based on the new sEHIs’ potency, binding kinetics, CNS drug-like properties, pharmacokinetic parameters and CNS target engagement for the in vivo efficacy testing. In Aim 2, the optimized sEHIs will be subjected to a 7-day dose range finding experiment and the sEHI, which can inhibit at least 90% of brain sEH with the lowest dose, will be selected for testing in mouse and rat Alzheimer’s disease models to determine their efficacy.

抽象的阿尔茨海默病影响着 600 万美国人，是美国第六大死因，并且在很大程度上预计 65 岁以上的人口将影响患者的生活质量，且尚无有效的治疗方法。到 2035 年，阿尔茨海默病患者的数量预计将增加两倍。因此，开发新的治疗方法来预防和/或治愈阿尔茨海默病的医疗需求尚未得到满足疾病。最近的研究表明，可溶性环氧化物水解酶（sEH）是阿尔茨海默病的新治疗靶点尽管较新的 sEH 抑制剂具有亚纳摩尔效力，但它们通常患有较差的血液循环。脑屏障渗透和不合适的物理特性作为高比例的 sEH 抑制/参与。需要引起显着的生物活性，具有高血脑屏障渗透性的 sEH 抑制剂和需要曝光。尽管 sEH 抑制剂的构效关系 (SAR) 已被广泛研究，但它们的对血脑屏障穿透性的影响很少被研究，现有的临床候选药物是预计 CNS 暴露较差，而大多数 SAR 研究都集中在两端的取代基上。我们将研究如何对 sEHI 进行修饰。连接体和其他修饰会影响其中枢神经系统药物特性和中枢神经系统暴露。纳入优化的修改，以进一步改善 sEHI 的药物特性和 CNS 暴露。该项目的研究人员将应用一种新颖的设计-测试-学习策略来指导新颖的 sEHI 的设计，使用我们的in- 用于筛选 sEHI 效力、结合动力学和体外药代动力学参数的室内测定。将使用我们既定的低剂量口服药物筛选候选者的 PK 特性和 CNS 暴露然后我们将进一步确定详细的药代动力学特性和 CNS。随着计划的进展，我们将进一步观察所选候选人的暴露参数。优化的候选者将根据新 sEHI 的效力、结合动力学、CNS 进行选择。用于体内功效测试的类药特性、药代动力学参数和中枢神经系统靶点参与。目标2，优化后的sEHI将进行为期7天的剂量范围寻找实验，并且sEHI可以以最低剂量抑制至少 90% 的大脑 sEH，将被选择用于小鼠和大鼠阿尔茨海默病的测试疾病模型以确定其功效。