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）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，在老年人中发展并导致记忆和认知过程丧失。全世界每年的反倾销费用估计为3154亿美元，这比世界上除8个国家以外的所有国家的预算都要高。目前还没有阻止AD进展的方法。一个中心假设是β-淀粉样蛋白（A2）肽的异常积累导致负责记忆的大脑区域的神经元变性。一种阻止或逆转疾病进展的潜在方法是通过抑制产生A2的酶来减少A2的产生。一个特别有吸引力的靶点是2-分泌酶，它切割淀粉样前体蛋白（APP）以产生A2的氨基末端。我们已经发现化合物E64 d和CA 074 Me在表达含有野生型β 2-分泌酶位点的APP的AD动物模型中是有效的，所述APP在大多数AD患者中发现。值得注意的是，我们发现E64 d和CA 074 Me在表达含有野生型2-分泌酶位点的人APP的转基因小鼠中改善记忆并减少脑淀粉样斑块，这两种特征都是AD。它们还减少了脑A2和CTF 2，这是由2-分泌酶切割产生的片段，这表明这些化合物通过抑制脑2-分泌酶活性起作用。E64 d和CA 074 Me分别是其酸形式E64 c和CA 074的乙酯和甲酯前药，其是体内活性剂。虽然结构上非常相似，但E64 c通常抑制半胱氨酸蛋白酶，而CA 074选择性抑制半胱氨酸蛋白酶，组织蛋白酶B。E64 d在首次开发用于肌营养不良症时被发现临床安全，但由于缺乏疗效而停止使用。由于CA 074是组织蛋白酶B特异性抑制剂，因此预期CA 074具有甚至更安全的特性。因此，E64 c和CA 074用于AD可能既有效又安全。需要新的E64 c和CA 074前药，以增加口服给药后的脑浓度。该基金将设计和合成两类新的前药，并在细胞和AD动物模型中对其进行评估。第一个将是制备E64 c和CA 074前药，其含有已知增加亲脂性和增加脑渗透可能性的酯。另一种是E64 c-和CA 074-胡芦巴碱化合物，它们通过将药物捕获在脑中同时促进其全身消除来增加脑与全身剂量比。将在正常和转基因AD动物模型中评价口服施用前药的功效。该项目有望通过引入一种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。具体而言，该项目将开发新的有效的阿尔茨海默病药物。目前，还没有有效的手段来阻止这种毁灭性疾病的进展，迫切需要新的药物。该项目将产生可能阻止或可能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。