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.

作者：William D. 摘要： 阿尔茨海默病(AD)是美国最大的未得到满足的医疗需求，也是 无法预防、治愈或减缓。Arviat制药公司正在开发口服小分子药物 12/15-脂氧合酶(12/15-LO)酶家族的抑制剂可减少小胶质细胞引起的神经炎症 因此，AD的进展缓慢。抑制12/15-LO活性以减少神经炎症 在帕金森氏病和孤儿儿童神经退行性疾病的人体临床试验中得到验证 人类基因组全关联研究，以及在AD和其他成年神经退行性变的动物模型中的研究 疾病。Vatiquone™是PI发现和开发的第一代12/15-LO抑制剂，目前正在使用 治疗儿童Leigh综合征，这是一种罕见的、否则会致命的儿童神经退行性疾病 以严重的神经炎症、小胶质细胞增多症和脑胶质细胞疤痕为特征。用他们的极致 神经炎，这一儿童群体可以被视为成人神经退行性变的加速模型 疾病(如阿尔茨海默病)。Vatiquone™不太适合治疗AD或帕金森氏症，导致了这些计划， 根据这一建议的SBIR，开发第二代口服小分子抑制剂12/15-LO与 显著优于Vatiquone™的疗效。这些努力将利用现有的并产生新的 知识产权，涵盖可能适用于治疗大量AD和其他疾病的新型药物 成人神经退行性疾病。除了内部开发的LO抑制剂外，Arviat还可以选择 产品组合涵盖5个化合物家族(7项美国专利(2013-2019年已发布)和几项未决申请)， 它们声称物质的组成具有与Vatiquone™相同的新的氧化还原作用机制。这 拟议的第一阶段SBIR研究将导致快速确定这6个家族的化合物的优先顺序，通过 迭代筛选漏斗，由以下特定目标组成：(1)制备≥100化合物，选择 彻底抽样专利组合；(2)测试这些化合物的效力和选择性，如12/15- 酶分析中的LO(VS 5-LO)抑制剂及(II)抑制活化人细胞因子的产生 小胶质细胞培养(IPSC-小胶质细胞)；(3)测试≥20化合物，基于AIM 2标准(IC50；50 在功能性神经保护中，12/15-LO为NM，5-LO为500 NM，IC50≤为75 NM) 实验(防止神经生长因子剥夺的小鼠初级神经元轴突变性)；和(4)检测≥6 根据AIM 3标准(IC50≤75 NM)改进的化合物，用于口服生物利用度和脑渗透性 在大鼠中(进展标准，脑/血浆比率≥为0.5%，口服利用度≥为20%)。如果成功，这将是 研究将确定至少3种化合物在第二阶段进行进一步评估，包括合成放大， 毒理学筛查、靶外活动、配方开发、确证PK和脑渗透性 研究，以及体内AD模型疗效研究，导致鉴定出一种用于IND使能的先导化合物 支持AD患者临床试验的研究，作为一种潜在的疾病修改治疗。