Novel Orally-Available Prodrugs for Alzheimer's Disease

 描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响超过550万美国老年人及其1300万护理人员。虽然在散发性患者中AD的确切原因尚不清楚，但在AD状态下增加的酶和蛋白质是药物开发的逻辑目标。鸟氨酸脱羧酶（ODC）是多胺合成的限速酶.除了ODC本身之外，与年龄匹配的对照组相比，AD大脑中的多胺水平也显著增加。多胺与NMDA介导的兴奋性毒性增加、内向整流活性降低和淀粉样β肽（AAPs）聚集增加有关。所有这些活动都可能导致AD脑中的神经元损失。 二氟甲基鸟氨酸（DFMO）是一种不可逆的ODC抑制剂，已被证明可降低脑中多胺的水平。然而，胃肠道毒性妨碍了高水平的DFMO给药，这就是为什么DFMO通常静脉输注给昏睡病患者。我们建议基于DFMO母体分子合成新的前药，其将在肠道中吸收，但不会引起胃肠道毒性。一旦这些前体药物进入血液，血液中的酯酶将切断额外的化学基团，以允许ODC的DFMO抑制剂循环。从我们自己的实验和其他人的实验来看，DFMO穿过血脑屏障进入大脑并抑制脑ODC。 在初步数据中，我们表明，给予DFMO的CVN阿尔茨海默病小鼠模型显着改善他们的学习和记忆行为，同时减少淀粉样斑块样和神经元缠结样结构。此外，另一组最近报道了DFMO给药在另一种AD小鼠模型中的类似治疗效果。DFMO在患有其他疾病的人类中的广泛使用加上这些新数据支持基于DFMO的前药可能是有效的抗阿尔茨海默病剂。我们建议合成的前药是新颖的，并且在成功测试如本建议中详述的活性之前，将是有用的，这是申请这些新物质组合物及其使用领域专利的两个主要标准。

 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.