Novel Orally-Available Prodrugs for Alzheimer's Disease

治疗阿尔茨海默病的新型口服前药

• 批准号: 8979556
• 负责人: MICHAEL PETER VITEK
• 金额: $ 22.5万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979556
• 关键词: Adverse effects; Affect; African Trypanosomiasis; Age; Alzheimer' s Disease; American; Amyloid beta-Protein; Animals; Behavior; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Caco-2 Cells; Caregivers; Cell Line; Cessation of life; Cleaved cell; DL-alpha-Difluoromethylornithine; Data; Degenerative Disorder; Disease; Dose; Encephalitis; Enzymes; Eye; Glucocorticoid Receptor; Half-Life; High Pressure Liquid Chromatography; Hour; Human; Inflammation; Injection of therapeutic agent; Lead; Learning; Legal patent; Mass Spectrum Analysis; Measures; Mediating; Memory; Memory Loss; Memory impairment; Molecular Weight; Mus; N-Methylaspartate; Neurofibrillary Tangles; Neurons; Oral; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Parents; Patients; Performance; Pharmaceutical Preparations; Plasma; Polyamines; Prodrugs; Production; Proteins; Putrescine; Relative (related person); Reporting; Retinal Ganglion Cells; Route; Senile Plaques; Site; Spermidine; Spermine; Stream; Structure; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Vertebral column; aged; alpha synuclein; analog; arginase; base; chemical group; compliance behavior; drinking water; drug development; esterase; excitotoxicity; gastrointestinal; human Huntingtin protein; improved; monolayer; mouse model; neuron loss; neurotoxicity; novel; overexpression; protective effect; public health relevance; research study

 DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a progressive neuro-degenerative disease that affects over 5.5 million aged Americans and their 13 million caregivers. While the exact cause of AD in sporadic patients is unknown, enzymes and proteins that increase in the AD state are logical targets for drug development. Ornithine Decarboxylase (ODC) is the rate- limiting enzyme for the synthesis of polyamines. In addition to ODC itself, levels of polyamines are also significantly increased in AD brains compared to age-matched controls. Polyamines have been associated with increased NMDA-mediated excitotoxicity, decreased inward rectifier activity, and increased aggregation of the amyloid beta peptide (Aß). All of these activities can contribute to neuronal loss in the AD brain. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ODC that is off-patent and has been shown to reduce brain levels of polyamines. However, gastrointestinal toxicities preclude dosing DFMO at high levels, which is why DFMO is typically intravenously infused in patients with sleeping sickness. We propose synthesizing novel prodrugs based upon the DFMO-parent molecule that will be absorbed in the gut, but do not cause gastrointestinal toxicities. Once these prodrugs are in the blood stream, esterases in the blood will cleave off the extra chemical groups to allow the DFMO inhibitor of ODC to circulate. From our own experiments and those of others, DFMO crosses the blood brain barrier to enter the brain and inhibit brain ODC. In preliminary data, we showed that administration of DFMO to the CVN mouse model of Alzheimer's disease significantly improves their learning and memory behavior while reducing amyloid plaque-like and neurofibrillary tangle-like structures. In addition, another group recent reported similar therapeutic effects of DFMO administration in another mouse model of AD. The extensive use of DFMO in humans with other diseases plus these new data support that prodrugs based on DFMO may be effective anti-Alzheimer's agents. The prodrugs that we are proposing to synthesize are novel, and pending successful testing for activity as detailed in this proposal, wil be useful, which are the two main criteria for patenting theses new compositions of matter and their field of use.

 描述（由适用提供）：阿尔茨海默氏病（AD）是一种进行性神经脱生的疾病，影响超过550万年龄的美国人及其1300万护理人员。尽管零星患者的AD的确切原因尚不清楚，但AD状态增加的酶和蛋白质是药物发育的逻辑靶标。鸟氨酸脱羧酶（ODC）是多胺合成的速率限制酶。除ODC本身外，与年龄匹配的对照相比，AD大脑的多胺水平也显着增加。多胺与NMDA介导的兴奋性毒性增加，内向整流剂活性降低以及淀粉样蛋白β胡椒（Aß）的聚集增加有关。所有这些活动都会导致AD大脑中的神经元丧失。二氟甲基氨酸氨酸（DFMO）是一种不可逆的ODC抑制剂，它是不利的，并且已被证明可以降低多胺的大脑水平。但是，胃肠道毒性排除了高水平的dFMO，这就是为什么DFMO通常会静脉内注入睡眠病患者的原因。我们建议基于将吸收在肠道中的DFMO分子的分子，但不会引起胃肠道毒性。一旦这些前药在血液中，血液中的酯酶将清除多余的化学基团，以使ODC的DFMO抑制剂循环。 DFMO从我们自己的实验和其他实验中，越过血脑屏障进入大脑并抑制脑ODC。在初步数据中，我们表明，对阿尔茨海默氏病CVN小鼠模型的DFMO给药可显着改善其学习和记忆行为，同时减少淀粉样蛋白斑块样和神经纤维纤维缠结的结构。此外，另一个小组最近在另一个小鼠AD模型中报道了DFMO给药的类似治疗作用。 DFMO在人类中的广泛使用以及其他疾病以及基于DFMO的这些新数据支持可能是有效的抗阿尔茨海默氏症药物。我们提议合成的前药是新颖的，并且在此提案中详细介绍的活动的成功测试中，这将是有用的，这是为物质及其使用领域提供专利的两个主要标准。