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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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.

摘要 阿尔茨海默病影响着600万美国人，是美国第六大死亡原因， 影响患者的生活质量，且无有效治疗方法。由于预计65岁以上的人口 到2035年，阿尔茨海默病患者的数量预计将增加至少两倍。 因此，存在未满足的医学需求，即开发新的治疗方法来预防和/或治愈阿尔茨海默病 疾病 近年来的研究表明可溶性环氧化物水解酶（sEH）是阿尔茨海默病治疗的新靶点 疾病虽然较新的sEH抑制剂具有亚纳摩尔的效力，但它们通常具有较差的血- 脑屏障渗透和不合适的物理性质。作为高百分比的sEH抑制/参与 需要引起显著的生物活性，具有高血脑屏障渗透性的sEH抑制剂， 曝光是必要的。 虽然sEH抑制剂的结构-活性关系（SAR）已被广泛研究，但它们的结构与活性之间的关系仍然是一个复杂的问题。 对血脑屏障渗透的影响很少被研究，现有的临床候选药物是 预计CNS暴露较差。虽然大多数SAR研究集中在两端的取代基上， 抑制剂，抑制剂的连接体很少被探索。我们将研究如何修改sEHI的 接头和其它修饰影响其CNS药物样性质和CNS暴露。我们将系统地 结合优化的修饰以进一步改善sEHI的药物样性质和CNS暴露。要求1 本项目的将采用一种新的设计-测试-学习策略来指导新的sEHIs的设计， 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。顶部 候选人将使用我们建立的低剂量口服给药系统筛选其PK特性和CNS暴露 盒式给药方法。然后，我们将进一步确定详细的药代动力学特性和CNS 所选候选人的曝光参数。随着计划的进展，我们将进一步观察 优化.将根据新sEHI的效价、结合动力学、CNS和免疫原性选择优化的候选物。 用于体内功效测试的药物样性质、药代动力学参数和CNS靶点接合。在 目的2，将优化的sEHI进行7天剂量范围探索实验， 以最低剂量抑制至少90%的脑sEH，将被选择用于在小鼠和大鼠阿尔茨海默氏症中进行测试 疾病模型，以确定其疗效。