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.

抽象的阿尔茨海默氏病影响了600万美国人，是全国第六大死亡原因，大大影响患者的生活质量，没有可用的有效治疗。随着65岁以上的人口预计到2035年，阿尔茨海默氏病患者的数量预计至少增加了两倍。因此，有未满足的医学需要开发新的治疗方法来预防和 /或治愈阿尔茨海默氏症疾病。最近的研究表明，固体环氧水解酶（SEH）是阿尔茨海默氏症的新型治疗靶标疾病。尽管较新的SEH抑制剂具有亚纳米尔效力，但它们通常患有血液不良脑屏障穿透和不合适的物理特性。作为SEH抑制 /参与的高比例需要引起重要的生物学活性，具有高血脑屏障渗透的SEH抑制剂和需要曝光。尽管已广泛研究了SEH抑制剂的结构活性关系（SARS），但对血脑屏障渗透的影响很少是研究的，现有的临床候选者是预计中枢神经系统暴露较差。虽然大多数SAR研究都集中在两端的副标题上抑制剂很少探索抑制剂的接头。我们将调查SEHI的修改接头和其他修饰会影响其中枢神经系统药物样性质和中枢神经系统的暴露。然后，我们将系统地纳入了优化的修改，以进一步改善SEHI的类似药物样特性和CNS暴露。目标1 该项目将采用一种新颖的设计测试策略来使用我们的In- 筛选Sehis效力，结合动力学和体外药代动力学参数的房屋测定。顶部候选人将使用我们已建立的低剂量口服的PK特性和中枢神经系统曝光筛选盒式剂量方法。然后，我们将进一步确定详细的药代动力学特性和CNS 选定候选人的暴露参数。随着计划的进行，我们将观察进一步观察优化。优化的候选人将根据新的Sehis的效力，具有约束力的动力学，CNS选择用于体内效率测试的药物样性质，药代动力学参数和中枢神经系统的目标参与。在 AIM 2，优化的SEHI将进行7天的剂量范围查找实验和SEHI，可以进行将至少抑制90％的脑SEH的最低剂量，以在小鼠和大鼠阿尔茨海默氏症中进行测试疾病模型以确定其效率。