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.

项目概要： 这项研究的目标是开发选择性和有效的人类 12/15-LOX 抑制剂， 这将探讨炎症在阿尔茨海默氏病（AD）中的作用，从而产生候选药物 严重的人类疾病缺乏任何治疗方法凸显了治疗这种疾病的新方法的必要性。 在众多新靶标中，12/15-脂氧合酶（12/15-LOX 或 15-LOX-1）脱颖而出。 原因是12/15-LOX在中枢神经系统中广泛表达，其蛋白水平与酶促有关。 AD 患者和临床诊断为轻度认知障碍的患者的活动显着升高 损伤，表明该途径早期参与 AD 发病机制。 12/15-LOX 的遗传缺失或早期药理学阻断可以预防认知障碍 此外，我们还发现转基因小鼠模型中出现类似 AD 的神经病理学。 还表明，12/15-LOX 药理学阻断在病理表型后是有益的 PD146176 是一种第一代专利到期的 12/15-LOX 抑制剂，可挽救学习和疾病。 记忆缺陷、降低 Aβ 水平和沉积、促进 tau 清除并改善突触完整性 然而，PD146176 不是选择性 12/15-LOX 抑制剂，并且对 3xTg 小鼠的活性较差。 因此，小鼠12/15-LOX相对于人类12/15-LOX，发现了更具选择性的下一代。 可申请专利的 12/15-LOX 抑制剂可以提供更好的多效性益处。 当前提案的三个目标是首先测试我们特征明确、已获得专利、有效、 选择性 12/15-LOX 抑制剂 ML351，针对我们的小鼠 AD 模型，具有优异的 ADME/PK 特性。 因此，我们将首先使用 ML351 重现之前在我们实验室发现的 PD146176 结果，以确认其为 其次，我们将发现针对 12/15-LOX 的其他候选分子。 开发针对 AD 的药物，利用我们的治疗方法来鉴定针对人类的新型选择性抑制剂 我们已经成功进行了 12/15-LOX 高通量 (HTP) 筛选。 与 NIH 合作，我们将筛选其新的 500,000 种化合物库中的前 1000 种化合物。 该筛选，测试针对体外人 12/15-LOX 的最佳有效/选择性命中，并确定它们的体内 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 特性并确认其 LOX/COX 选择性。 ML351 已被证明可以穿过血脑屏障并防止中风损伤，我们正在 我们相信这些研究将表明 ML351 可以预防 AD 症状，因此具有出色的疗效 有机会成为针对 AD 的有效治疗工具。