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，在很大程度上 在没有有效治疗方法的情况下影响患者的生活质量。随着65岁以上人口的预测 到2035年将增加两倍，阿尔茨海默病患者的数量预计将增加至少两倍。 因此，开发新的治疗方法来预防和或治愈阿尔茨海默氏症是一个尚未得到满足的医学需求 疾病。 最近的研究表明，可溶性环氧化物水解酶(SEH)是治疗阿尔茨海默病的新靶点 疾病。尽管较新的sEH抑制剂具有亚纳摩尔效力，但它们通常会患上血液质量不佳-- 脑屏障穿透和不合适的物理特性。作为sEH抑制/参与的高百分比 需要诱导显著的生物活性，具有高血脑屏障的sEH抑制剂和 暴露是必要的。 尽管sEH抑制剂的构效关系(SARS)已经被广泛研究，但它们的 对血脑屏障穿透的影响很少被研究，现有的临床候选方案是 预测有较差的中枢神经系统暴露。虽然大多数的SAR研究都集中在分子两端的取代基上 抑制剂是抑制剂的连接物，很少有人对其进行研究。我们将调查sEHI的修改如何 接头和其他修饰会影响其中枢神经系统类药物特性和中枢神经系统暴露。然后我们将系统地 纳入优化的修改，以进一步改善sEHI的类药物特性和中枢神经系统暴露。目标1 该项目将应用一种新颖的设计-测试-学习策略来指导新颖的SSHIS的设计，使用我们的in-in- House试验筛选sEHIS效价、结合动力学和体外药动学参数。顶层 候选人将使用我们建立的低剂量口服对他们的PK特性和中枢神经系统暴露进行筛查 盒式给药方法。然后，我们将进一步确定详细的药代动力学性质和中枢神经系统 选定候选对象的曝光参数。随着项目的进展，我们将进一步观察 优化。将根据新的sEHIs的效力、结合动力学、CNS来选择优化的候选者 体内药效试验的类药物性质、药代动力学参数和CNS靶点接合。在……里面 目的2，对优化后的sEHIs进行为期7天的剂量范围发现实验和sEHI，它可以 以最低的剂量抑制至少90%的脑sEH，将被选为在小鼠和大鼠阿尔茨海默氏症中进行测试 疾病模型来确定它们的疗效。