Novel Orally-Available Prodrugs for Alzheimer's Disease

 描述(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550万美国老年人和他们的1300万照顾者。虽然散发性患者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合乎逻辑的靶点。鸟氨酸脱羧酶(ODC)是合成多胺的限速酶。除了ODC本身，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蛋白聚集性增加有关。所有这些活动都可能导致阿尔茨海默病大脑中神经元的丢失。二氟甲基鸟氨酸(DFMO)是一种不可逆的ODC抑制剂，已过专利，已被证明可降低大脑中多胺的水平。然而，胃肠道毒性排除了高剂量的DFMO，这就是为什么DFMO通常被静脉注射给患有昏睡病的患者。我们建议基于DFMO母体分子合成新的前体药物，该分子将被肠道吸收，但不会引起胃肠道毒性。一旦这些前体药物进入血流，血液中的酯酶就会分解掉额外的化学基团，使ODC的DFMO抑制剂得以循环。从我们自己和其他人的实验来看，DFMO跨越血脑屏障进入大脑，抑制大脑ODC。在初步数据中，我们显示，给阿尔茨海默病CVN小鼠模型服用DFMO显著改善了它们的学习和记忆行为，同时减少了淀粉样斑块和神经原纤维缠绕样结构。此外，另一个小组最近报道了在另一种AD小鼠模型中给予DFMO的类似治疗效果。DFMO在患有其他疾病的人类中的广泛使用，加上这些新的数据支持，基于DFMO的前药可能是有效的抗阿尔茨海默氏剂。我们建议合成的前药是新的，在本提案中详细说明的活性测试成功之前，将是有用的，这是为这些新物质组成及其使用领域申请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.