Discovery of 12/15-lipoxygenase inhibitors to suppress neuroinflammation and slow disease progression in Alzheimer's disease

发现 12/15-脂氧合酶抑制剂可抑制阿尔茨海默病的神经炎症并减缓疾病进展

• 批准号: 10255682
• 负责人: William Dvorak Shrader
• 金额: $ 45.01万
• 依托单位: ACUREX THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255682
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Animal Model; Anti-Inflammatory Agents; Arachidonate 15-Lipoxygenase; Biochemical; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Cause of Death; Cellular Assay; Cessation of life; Child; Childhood; Cicatrix; Clinic; Clinical Trials; Collection; Cytokine Suppression; Data; Development; Disease; Disease Progression; Doctor of Philosophy; Dose; Drug Kinetics; Endotoxins; Enzymes; Evaluation; Family; Formulation; Generations; Goals; Hippocampus (Brain); Human; Human Genome; Inflammation; Intellectual Property; Interleukin-1 beta; Interleukin-6; Intravenous; Lead; Legal patent; Leigh Disease; Lipids; Lipoxygenase Inhibitors; Measures; Medical; Memory; Microglia; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Orphan; Oxidation-Reduction; Parkinson Disease; Patients; Penetrance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Population; Preparation; Prevention; Process; Production; Rattus; Research; Research Support; Sampling; Signal Transduction; Small Business Innovation Research Grant; Stress; Symptoms; TNF gene; Testing; Toxicology; Transgenic Organisms; Variant; axonal degeneration; base; brain tissue; cognitive function; cytokine; efficacy study; efficacy testing; family structure; genetic association; genome wide association study; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; morris water maze; mouse model; nervous system disorder; neuroinflammation; neuroprotection; novel; novel therapeutics; prevent; scale up; screening; small molecule inhibitor; β-amyloid burden

Shrader, William D. Abstract: Alzheimer's disease (AD) is the largest unmet medical need in the US and the only major cause of death that cannot be prevented, cured, or slowed. Arviat Pharmaceuticals, Inc. is developing oral small-molecule inhibitors of the 12/15-lipoxygenase (12/15-LO) enzyme family to reduce microglia driven neuroinflammation and, thereby, slow progression of AD. Inhibition of 12/15-LO activity to reduce neuroinflammation has been validated in human clinical trials in Parkinson's disease and orphan pediatric neurodegenerative diseases, in human genome wide association studies, and in animal models of AD and other adult neurodegenerative diseases. Vatiquinone™, a first generation 12/15-LO inhibitor discovered and developed by the PI, is now used to treat children with Leigh syndrome, a rare, otherwise fatal pediatric neurodegenerative disease characterized by severe neuroinflammation, microgliosis, and gliotic scarring of the brain. With their extreme neuroinflammation, this pediatric population can be viewed as accelerated models of adult neurodegenerative disease (e.g. AD). Vatiquinone™ is not well-suited for treating AD or Parkinson's disease, leading to the plans, under this proposed SBIR, to develop second-generation oral small-molecule inhibitors of 12/15-LO with significantly greater efficacy than Vatiquinone™. These efforts will leverage existing and generate new intellectual property, covering novel agents potentially suitable for treating large populations with AD and other adult neurodegenerative diseases. In addition to LO inhibitors developed internally, Arviat has an option on a portfolio covering 5 compound families (7 US patents (issued 2013–2019) and several pending applications), which claim compositions of matter with the same novel redox mechanism of action as Vatiquinone™. This proposed Phase I SBIR research will lead to rapid prioritization of compounds from these 6 families, through an iterative screening funnel, consisting of these Specific Aims: (1) To prepare ≥100 compounds, selected to thoroughly sample the patent portfolios; (2) To test these compounds for (i) potency and selectivity as 12/15- LO (vs 5-LO) inhibitors in enzyme assays and (ii) suppression of cytokine production in activated human microglial cultures (iPSC-microglia); (3) To test ≥20 compounds, advanced based on Aim 2 criteria (IC50<50 nM for 12/15-LO, and >500 nM for 5-LO and IC50 ≤75 nM in cellular assays), in a functional neuroprotection assay (prevention of axonal degeneration in NGF-deprived mouse primary neurons); and (4) To test ≥6 compounds, advanced based on the Aim 3 criterion (IC50≤75 nM), for oral bioavailability and brain permeability in rats (criteria for advancement, brain/plasma ratios ≥0.5 and oral availability ≥20%). If successful, this research will identify at least 3 compounds for further evaluation in Phase II, to include synthetic scale-up, toxicology screening, off-target activities, formulation development, confirmatory PK and brain permeability studies, and in vivo AD model efficacy studies, leading to identification of a lead compound for IND-enabling research supporting clinical trials in AD patients, as a potential disease-modifying treatment.

Shrader，William D. 抽象的： 阿尔茨海默氏病（AD）是美国最大的未满足医疗需求，也是唯一的主要死亡原因 无法预防，治愈或放慢。 Arviat Pharmaceuticals，Inc。正在开发口服小分子 12/15-脂氧酶（12/15-LO）酶的抑制剂，以减少小胶质细胞驱动神经炎症 而且，AD的进展缓慢。抑制12/15-LO活性以减少神经炎症的活性已是 在帕金森氏病和孤儿小儿神经退行性疾病的人类临床试验中得到了验证 人类基因组广泛的关联研究以及AD和其他成年神经退行性的动物模型 疾病。 Vatiquinone™是PI发现和开发的第一代12/15-LO抑制剂，现已使用 为了治疗Leigh综合征的儿童，这是一种罕见的，否则致命的小儿神经退行性疾病 以严重的神经炎症，小胶质细胞症和大脑的胶质性疤痕为特征。与他们的极端 神经炎症，该小儿种群可以看作是成年神经退行性的加速模型 疾病（例如AD）。 Vatiquinone™不适合治疗广告或帕金森氏病，导致计划， 在此拟议的SBIR下，以12/15-lo开发第二代口服小分子抑制剂 效率明显高于Vatiquinone™。这些努力将利用现有的并产生新的 知识产权，涵盖可能适合用AD和其他其他人群治疗大量人群的新型代理商 成人神经退行性疾病。除了内部开发了LO抑制剂外，Arviat还可以选择 投资组合涵盖5个化合物家庭（7项美国专利（2013 - 2019年发布）和几个待定申请）， 该物质具有与Vatiquinone™相同的新型氧化还原作用机理的组成。这 拟议的第一阶段SBIR研究将导致这6个家族的化合物快速优先考虑 由这些特定目的组成的迭代筛选漏斗：（1）准备≥100种化合物，选择为 彻底品尝​​专利组合； （2）测试这些化合物的效力和选择性为12/15-- 酶测定中的LO（VS 5-LO）抑制剂，以及（ii）激活人的细胞因子产生 小胶质细胞培养物（IPSC-Microglia）； （3）测试≥20种化合物，基于AIM 2标准（IC50 <50）先进 在功能性神经保护中，在12/15-LO中进行12/15-LO，5-LO和IC50≤75nm的Nm，IC50≤75nm） 测定（预防NGF剥夺小鼠原发性神经元中的轴突变性）； （4）测试≥6 基于AIM 3标准（IC50≤75nm）的化合物，用于口服生物利用度和脑部通透性 在大鼠（进步的标准，大脑/血浆比≥0.5和口服可用性≥20％）中。如果成功，这 研究将至少识别3种化合物，以进一步评估II阶段，包括合成规模， 毒理学筛查，脱靶活动，配方开发，确认PK和大脑渗透性 研究和体内AD模型效率研究，导致识别铅化合物以辅助 研究支持AD患者的临床试验的研究，作为一种潜在的疾病改良治疗。