Prodrugs to treat Alzheimer's disease

治疗阿尔茨海默病的前药

• 批准号: 7762713
• 负责人: GREGORY R HOOK
• 金额: $ 10.16万
• 依托单位: AMERICAN LIFE SCIENCE PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762713
• 关键词: Acids; Alzheimer' s Disease; American; Amyloid beta-Protein Precursor; Animal Model; Animals; Anus; Asses; Behavior; Biological Assay; Blood - brain barrier anatomy; Brain; Brain region; Budgets; Cathepsins B; Cattle; Cavia; Cell Culture Techniques; Cells; Characteristics; Charge; Chemicals; Chemistry; Child; Chromaffin Cells; Cleaved cell; Cognitive; Country; Cysteine Protease; Cysteine Proteinase Inhibitors; Data; Defect; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Industry; Drug Kinetics; Enzymes; Esters; Excretory function; Experimental Designs; Expressed Sequence Tags; Family; Grant; Human; Hydrolysis; Individual; Japan; Lead; Life; London; Measures; Memory; Memory Loss; Memory impairment; Modeling; Monitor; Mus; Muscular Dystrophies; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Oral; Oral Administration; Pathology; Pathway interactions; Patients; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Process; Prodrugs; Production; Public Health; Research; Secretory Vesicles; Senile Plaques; Site; Specific qualifier value; Specificity; System; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Translating; Translational Research; Work; abeta accumulation; aged; amyloid peptide; base; cost; design; drug development; experience; improved; in vivo; inhibitor/antagonist; lipophilicity; morris water maze; mouse model; neuron loss; neurotoxic; oxidation; public health relevance; secretase; small molecule; trigonelline; volunteer

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder that develops in aged individuals and causes loss of memory and cognitive processes. The world-wide cost of AD is estimated to be $315.4 billion annually, which is greater than the budget of all but eight of the world's countries. There is currently no means of stopping the progression of AD. A central hypothesis is that the abnormal accumulation of beta-amyloid (A2) peptides causes neuronal degeneration in brain regions responsible for memory. A potential means of stopping, or possibly reversing, the progression of the disease is to reduce A2 production by inhibiting the enzymes that produce it. A particularly attractive target for doing this is the 2-secretase, which cleaves the amyloid precursor protein (APP) to produce the amino terminal end of A2. We have found that the compounds, E64d and CA074Me are efficacious in AD animal models expressing APP containing the wild-type 2-secretase site, which is found in most AD patients. Significantly, we discovered that E64d and CA074Me improve memory and reduce brain amyloid plaques, both characteristics of AD, in transgenic mice expressing human APP containing the wild-type 2-secretase site. They also reduced brain A2 and CTF2, a fragment produced by 2-secretase cleavage, which suggests that the compounds act by inhibiting brain 2-secretase activity. E64d and CA074Me are the ethyl and methyl ester prodrugs, respectively, of their acid forms, E64c and CA074, which are the active in vivo agents. Although structurally very similar, E64c inhibits cysteine proteases generally whereas CA074 selectively inhibits the cysteine protease, cathepsin B. E64d was found clinically safe to use when first developed for muscular dystrophy but was discontinued due to lack of efficacy. CA074 is expected to have an even safer profile because it is a cathepsin B specific inhibitor Thus, E64c and CA074 are likely to be both efficacious and safe to use for AD. New E64c and CA074 prodrugs are needed that increase the brain concentrations after oral administration. This grant will design and synthesize two new classes of such prodrugs and evaluate them in cell and AD animal models. The first will be to make E64c and CA074 prodrugs containing esters known to increase the lipophilicity and increase the likelihood of brain penetration. The other is E64c- and CA074-trigonelline compounds, which increase the brain-to- systemic dose ratio by trapping the drug in the brain while facilitating its systemic elimination. The efficacy of orally administering the prodrugs will be evaluated in normal and transgenic AD animal models. This project promises to have a major impact on AD drug translational research by ushering in an entirely new class of cysteine protease inhibitor AD drugs. PUBLIC HEALTH RELEVANCE: The project is relevant to the public health. Specifically, this project will develop new and effective Alzheimer's disease drugs. Currently, there is no effective means of stopping the progress of this devastating disease and there is an urgent need for new drugs that do so. This project will result in drugs that may halt or, possibly, reverse the progression of the disease. As such, the project has enormous potential for improving the lives of millions of Americans and their families.

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，在老年人中发生并导致记忆和认知过程丧失。全球范围内的 AD 成本每年估计为 3154 亿美元，高于世界上除 8 个国家外的所有国家的预算。目前没有办法阻止 AD 的进展。一个中心假设是，β-淀粉样蛋白 (A2) 肽的异常积累会导致负责记忆的大脑区域的神经元变性。阻止或可能逆转疾病进展的一种潜在方法是通过抑制产生 A2 的酶来减少 A2 的产生。执行此操作的一个特别有吸引力的目标是 2-分泌酶，它裂解淀粉样前体蛋白 (APP) 以产生 A2 的氨基末端。我们发现化合物 E64d 和 CA074Me 在表达含有野生型 2-分泌酶位点的 APP 的 AD 动物模型中有效，该位点存在于大多数 AD 患者中。值得注意的是，我们发现在表达含有野生型 2-分泌酶位点的人 APP 的转基因小鼠中，E64d 和 CA074Me 可以改善记忆力并减少脑淀粉样斑块，这都是 AD 的特征。他们还减少了大脑 A2 和 CTF2（2-分泌酶裂解产生的片段），这表明这些化合物通过抑制大脑 2-分泌酶活性发挥作用。 E64d和CA074Me分别是其酸形式的乙酯和甲酯前药，E64c和CA074是体内活性剂。虽然结构非常相似，但 E64c 通常抑制半胱氨酸蛋白酶，而 CA074 选择性抑制半胱氨酸蛋白酶组织蛋白酶 B。E64d 在首次开发用于肌营养不良症时被发现在临床上可以安全使用，但由于缺乏疗效而停止使用。 CA074 预计具有更安全的特性，因为它是组织蛋白酶 B 特异性抑制剂。因此，E64c 和 CA074 可能对 AD 有效且安全。需要新的 E64c 和 CA074 前药来增加口服后脑内的浓度。这笔赠款将设计和合成两类新的此类前药，并在细胞和 AD 动物模型中对其进行评估。第一个是制造含有酯的 E64c 和 CA074 前药，已知这些酯可以增加亲脂性并增加脑渗透的可能性。另一种是E64c-和CA074-葫芦巴碱化合物，它们通过将药物捕获在大脑中来增加大脑与全身的剂量比，同时促进其全身消除。将在正常和转基因AD动物模型中评估口服前药的功效。该项目有望通过引入一类全新的半胱氨酸蛋白酶抑制剂 AD 药物，对 AD 药物转化研究产生重大影响。公共卫生相关性：该项目与公共卫生相关。具体来说，该项目将开发新的有效的阿尔茨海默病药物。目前，还没有有效的方法来阻止这种毁灭性疾病的进展，因此迫切需要新的药物来阻止这种破坏性疾病的发展。该项目将研制出可能阻止或逆转疾病进展的药物。因此，该项目具有改善数百万美国人及其家庭生活的巨大潜力。