Discovery of 12/15-Lipoxygenase Inhibitors for Alzheimer's Disease

发现治疗阿尔茨海默病的 12/15-脂氧合酶抑制剂

• 批准号: 9763402
• 负责人: Theodore R Holman
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763402
• 关键词: 3xTg-AD mouse; Accounting; Affect; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Arachidonate 15-Lipoxygenase; Binding Proteins; Biological Assay; Blood - brain barrier anatomy; Cells; Cellular Assay; Characteristics; Chemicals; Clinical; Collaborations; Data; Dementia; Deposition; Development; Disease; Disease Progression; Disease model; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Excretory function; Future; Generations; Genetic; Goals; Human; Impaired cognition; In Vitro; Inflammation; Isoenzymes; LOX gene; Laboratories; Lead; Learning; Legal patent; Libraries; Ligands; Lipoxygenase; Lipoxygenase Inhibitors; Liquid substance; Memory impairment; Metabolic; Metabolic Clearance Rate; Metabolism; Molecular Bank; Monitor; Mus; Neuraxis; Neurons; Oral; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Plasma; Prevention; Process; Property; Prostaglandin-Endoperoxide Synthase; Proteins; Research; Role; Series; Solubility; Stroke; Symptoms; Synapses; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; United States; United States National Institutes of Health; absorption; aged; aqueous; base; behavioral impairment; chemical property; clinical Diagnosis; cost; disease phenotype; drug candidate; drug development; effective therapy; experimental study; high throughput screening; human disease; improved; in vivo; inhibitor/antagonist; mild cognitive impairment; mouse model; neuropathology; next generation; novel; novel strategies; novel therapeutics; off-patent; prevent; repository; screening; small molecule libraries; tau Proteins; therapeutic development; therapeutic target; tool

PROJECT SUMMARY: The principle goal of this research is to develop selective and potent human 12/15-LOX inhibitors, which will probe the role of inflammation in Alzheimer's disease (AD), leading to drug candidates for this devastating human disease. The lack of any therapeutic for AD highlights the need for new approaches to its treatment. Among the novel targets, 12/15-lipoxygenase (12/15-LOX or 15-LOX-1) stands out for numerous reasons. 12/15-LOX is widely expressed in the central nervous system, and its protein levels and enzymatic activity are significantly elevated in patients with AD and those with a clinical diagnosis of mild cognitive impairment, suggesting an early involvement of the pathway in AD pathogenesis. Our laboratories have shown that genetic absence or the early pharmacological blockade of 12/15-LOX prevents cognitive impairment and the development of AD-like neuropathology in transgenic mouse models of the disease. In addition, we have also shown that the 12/15-LOX pharmacological blockade is beneficial after pathological phenotype of the disease has developed. PD146176, a first-generation, off-patent 12/15-LOX inhibitor, rescues learning and memory deficits, reduces Aβ levels and deposition, facilitates tau clearance and improves synaptic integrity in aged 3xTg mice. However, PD146176 is not a selective 12/15-LOX inhibitor and it has poor activity against the mouse 12/15-LOX relative to the human 12/15-LOX. Therefore, discovering more selective next-generation 12/15-LOX inhibitors that are patentable may provide better pleiotropic benefits. The three objectives of the current proposal are to first test our well-characterized, patented, potent, selective 12/15-LOX inhibitor, ML351, against our mouse AD model. ML351 has excellent ADME/PK properties so we will first reproduce the PD146176 results found previously in our laboratory with ML351 to confirm it as a viable AD therapeutic against 12/15-LOX. Second, we will discover additional candidate molecules toward therapeutic development against AD, utilizing our assays to identify novel, selective inhibitors for the human 12/15-LOX. We have already performed a successful 12/15-LOX high-throughput (HTP) screen in collaboration with the NIH of their new 500,000 compound library. We will screen the top 1000 compounds of this screen, test the top potent/selective hits against in vitro human 12/15-LOX, and determine their in vivo effectiveness against cultured mouse HT-22 neuronal cells. Third, we will optimize our newly discovered 12/15- LOX inhibitors for their ADME and PK properties and confirm their LOX/COX selectivity. Considering that ML351 has already been shown to cross the blood-brain barrier and protect against stroke damage, we are confident these studies will show that ML351 protects against AD symptoms and thus have an excellent chance of becoming an effective therapeutic tool against AD.

项目摘要： 这项研究的主要目标是开发选择性和潜在的人类12/15-lox抑制剂，即 这将探讨炎症在阿尔茨海默氏病（AD）中的作用，导致候选药物 毁灭性的人类疾病。缺乏广告疗法的任何疗法都强调了新方法的需求 治疗。在新的靶标中，12/15-脂氧合酶（12/15-LOX或15-LOX-1）脱颖而出 原因。 12/15-lox在中枢神经系统中广泛表达，其蛋白质水平和酶促水平 AD患者和患有轻度认知临床诊断的患者的活性显着升高 损害，表明该途径在AD发病机理中的早期参与。我们的实验室已经表明 遗传缺失或12/15-Lox的早期药物阻断可防止认知障碍和 在该疾病的转基因小鼠模型中，AD样神经病理学的发展。此外，我们还有 还表明，在病理表型的病理表型之后，12/15-Lox药物阻滞是有益的 疾病已经发展。 PD146176，是第一代，非应有的12/15-Lox抑制剂，营救学习和 记忆定义，降低Aβ水平和沉积，促进tau间隙并提高突触完整性 年龄3XTG小鼠。但是，PD146176不是选择性的12/15-lox抑制剂，它的活性较差 小鼠12/15-lox相对于人类12/15-lox。因此，发现更有选择性的下一代 可申请专利的12/15-LOX抑制剂可以提供更好的多效益处。 当前提案的三个对象是首先测试我们的特色，专利，潜力， 选择性12/15-Lox抑制剂ML351，针对我们的鼠标AD模型。 ML351具有出色的ADME/PK属性 因此，我们将首先复制以前在我们的实验室中使用ML351的PD146176结果，以确认它为 可行的广告疗法针对12/15-lox。其次，我们将发现其他候选分子 使用我们的评估来识别针对人类的新颖的选择性抑制剂的治疗性开发 12/15-lox。我们已经完成了成功的12/15-Lox高通量（HTP）屏幕 与他们新的500,000复合库的NIH合作。我们将筛选前1000个化合物的 在此屏幕上，测试对体外人类12/15-lox的最高电位/选择性命中，并确定其体内 针对培养的小鼠HT-22神经元细胞的有效性。第三，我们将优化新发现的12/15-- LOX抑制剂的ADME和PK性质，并确认其LOX/COX选择性。考虑到这一点 ML351已经显示出可以越过血脑屏障并防止中风损害，我们是 这些研究充满信心，将表明ML351可以防止AD症状，因此具有出色的 成为反对AD的有效治疗工具的机会。