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（由申请人提供）：阿尔茨海默氏病 (AD) 是一种进行性神经退行性疾病，影响着超过 550 万美国老年人及其 1300 万护理人员，虽然散发性患者患 AD 的确切原因尚不清楚，但阿尔茨海默病中的酶和蛋白质会增加。 AD 状态是药物开发的合理目标。鸟氨酸脱羧酶 (ODC) 是多胺合成的限速酶。除了 ODC 本身外，多胺的水平也是如此。与年龄匹配的对照相比，AD 大脑中的多胺含量显着增加，与 NMDA 介导的兴奋性毒性增加、内向整流活性降低以及淀粉样蛋白 β 肽 (Aß) 聚集增加有关，所有这些活动都可能导致 AD 患者的神经元损失。二氟甲基鸟氨酸 (DFMO) 是一种不可逆的 ODC 抑制剂，已被证明可以降低大脑中的多胺水平。胃肠道毒性阻碍了高剂量的 DFMO 给药，这就是为什么 DFMO 通常被静脉注射给昏睡病患者的原因，我们建议基于 DFMO 母体分子合成新型前药，该药物将在肠道中吸收，但不会引起胃肠道毒性。一旦这些前药进入血流，血液中的酯酶就会裂解掉多余的化学基团，使 ODC 的 DFMO 抑制剂能够根据我们自己和其他人的实验，DFMO 可以穿过血脑屏障进入大脑并抑制大脑 ODC。初步数据表明，给阿尔茨海默病 CVN 小鼠模型施用 DFMO 可以显着改善其学习和记忆能力。此外，另一个研究小组最近报告了在另一种 AD 小鼠模型中使用 DFMO 具有类似的治疗效果，同时还减少了淀粉样斑块样和神经原纤维缠结样结构。新数据支持基于 DFMO 的前药可能是有效的抗阿尔茨海默病药物。我们提议合成的前药是新颖的，并且在成功测试本提案中详述的活性之前，将是有用的，这是两个主要标准。为这些新的物质组合物及其使用领域申请专利。