Development of a Novel Therapeutic for Alzheimer' Disease

阿尔茨海默氏病新疗法的开发

• 批准号: 8463781
• 负责人: MARK Anthony LOVELL
• 金额: $ 10万
• 依托单位: COPLEX THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463781
• 关键词: APP-PS1; Active Immunization; Address; Adverse effects; Adverse event; Age; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animals; Antibodies; Aricept; Attenuated; Behavior; Behavioral; Brain; Calcium Channel; Calcium Channel Blockers; Cardiovascular system; Cell Culture Techniques; Cholinesterase Inhibitors; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Cognitive; Data; Deposition; Development; Diet; Diffusion Magnetic Resonance Imaging; Dihydropyridines; Disease; Disease Progression; Edema; Evaluation; Formic Acids; Future; Generations; Human; Image; Immunohistochemistry; Immunotherapy; In Vitro; Kentucky; Lactams; Lead; Learning; Liquid substance; Magnetic Resonance Imaging; Measures; Mediating; Memantine; Mus; N-Methylaspartate; Nifedipine; Passive Immunization; Pathogenesis; Patients; Pharmaceutical Preparations; Process; Production; Proteins; Recovery; Rodent; Side; Specimen; Staging; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; Transgenic Mice; United States Food and Drug Administration; Universities; Weight; alpha secretase; amyloid precursor protein processing; base; behavior test; beta-site APP cleaving enzyme 1; cerebrovascular; commercialization; dihydropyridine; drug candidate; drug development; efficacy testing; gamma secretase; human subject; improved; in vivo; mild neurocognitive impairment; morris water maze; mouse model; nicastrin protein; notch protein; novel; novel therapeutics; presenilin-1; response

DESCRIPTION (provided by applicant): Traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel lactam derivative of the commonly prescribed 1,4 dihydropyridine calcium channel blocker nifedipine (1-acetyl-2,4- dimethylbenzo[c][2,7]naphthyridin-5(6H)-one; NFD-L) that lacks calcium channel blocking capacity but significantly decreases Ass1-42 production by increasing levels of alpha-secretase (ADAM-10) and decreasing levels of presenilin-1 and nicastrin (components of the gamma secretase complex). Based on our preliminary data, the hypothesis to be tested in this proposal is that NFD-L lacks calcium channel blocking capacity and potential adverse cardiovascular side effects, effectively diminishes generation of A?1-42 by increasing levels of alpha-secretase (ADAM-10) processing of APP and by decreasing levels of proteins involved in A?1-42 processing (presenilin-1 and nicastrin), and improves spatial learning in a mouse model of amyloid deposition. In addition, we hypothesize that NFD-L does not lead to microhemorrhages or edema (amyloid related imaging abnormalities; ARIA) that are associated with immunotherapy mediated A? clearance. If successful, the data obtained in this proposal would further clarify the effects of NFD-L on A? processing and confirm whether or not it induces ARIA which would address FDA concerns and potentially increase the likelihood of successful commercialization of NFD-L. PUBLIC HEALTH RELEVANCE: Currently two classes of medications are FDA approved for use by Alzheimer's disease (AD) patients including cholinesterase inhibitors (Aricept) and an N-methyl-D-aspartate (NMDA) antagonist (Memantine). Although these therapeutics show clinical benefit in some patients, many do not respond. Additionally, these drugs do not significantly modify disease progression and perhaps more importantly are not approved for patients at earlier stages of the disease (mild cognitive impairment; MCI). For these reasons there is a critical need to identify additional therapeutics that can be initiated early in the disease progression to alter the pathogenesis of the disease. Preliminary and future studies described in this proposal aim to test the efficacy of a novel derivative of a commonly prescribed calcium channel blocker in a mouse model of amyloid beta (A¿1-42) deposition (APP/PS1 mice) and to determine if the novel therapeutic leads to microhemorrhages or edema as has been observed in studies using A¿ immunotherapy. If successful, the results of the proposed studies would address concerns that have been raised by the FDA regarding amyloid lowering agents and further support testing of the compound in clinical trials.

描述（适用提供）：阿尔茨海默氏病的传统药物开发方法变得越来越昂贵，并且在许多情况下令人失望的失败。基于初步的体外和体内研究，我们确定了通常处方1,4二氢吡啶钙通道阻滞剂硝基胺（1-乙酰基-2,4-二甲基苯甲酰苯甲苯苯甲酸酯[C] [c] [2,7] naphthythythythythyridin-5（6H） - nfs-nfs; nFd-ldd-ldd-ldd-lfs canclist; ASS1-42通过增加α-分泌酶（ADAM-10）的水平以及降低Presenilin-1和Nicastrin（Gamma泌尿酶复合酶的成分）的水平降低。根据我们的初步数据，在该提议中要检验的假设是，NFD-L缺乏钙通道阻塞能力和潜在的不良心血管副作用，从而有效地减少了？1-42的生成？1-42通过增加α-泌尿药酶（ADAM-10）的水平（ADAM-10）的水平（ADAM-10）的水平，并降低了应用程序的水平和蛋白质的水平，并确定了质量和1-42的水平（及其质量​​）。在淀粉样蛋白沉积的小鼠模型中改善空间学习。此外，我们假设NFD-L不会导致与免疫疗法介导的A？清除。如果成功，此提案中获得的数据将进一步阐明NFD-L对A的影响？处理并确认它是否影响芳香，这将解决FDA关注点并有可能增加NFD-L成功商业化的可能性。 公共卫生相关性：目前，Alzheimer疾病（AD）患者（包括胆碱酯酶抑制剂（ARICEPT））和N-Methyl-D-天冬氨酸（NMDA）拮抗剂（美容）批准了两类药物。此外，这些药物不会显着改变疾病的进展，更重要的是，在疾病早期阶段（轻度认知障碍； MCI）的患者也没有得到批准。由于这些原因，迫切需要确定可以在疾病进展早期开始以改变疾病发病机理的其他疗法。该提案中描述的初步和未来研究旨在测试在淀粉样β（A¿1-42）沉积的小鼠模型中，通常开处方的钙通道阻滞剂的新颖衍生物（APP/PS1小鼠）的有效性，并确定新颖的热量导致微疗法或湿气的研究是否已在研究中使用了Immyun Poseps，该研究是否已在研究中观察到。如果成功的话，拟议的研究结果将解决FDA对淀粉样蛋白降低剂的关注，并在临床试验中进一步支持该化合物的测试。