Prodrugs to treat 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，在老年人中发展，并导致记忆和认知过程的丧失。据估计，全球每年的AD费用为3154亿美元，这一数字超过了世界上除八个国家外的所有国家的预算。目前没有办法阻止阿尔茨海默病的发展。一个中心假说是，β-淀粉样蛋白(A2)多肽的异常积累导致负责记忆的大脑区域的神经元退化。阻止或可能逆转疾病发展的一个潜在方法是通过抑制产生A2的酶来减少A2的产生。这样做的一个特别吸引人的目标是2-分泌酶，它裂解淀粉样前体蛋白(APP)，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AD动物模型中是有效的，而野生型2-分泌酶位点在大多数AD患者中都存在。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改善了记忆，减少了脑淀粉样斑块，这两个都是AD的特征。它们还减少了大脑A2和CTF2，这是一种由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-分泌酶的活性而起作用。E64d和CA074Me分别是其酸性形式的乙酯和甲酯前药，E64c和CA074是体内活性药物。虽然在结构上非常相似，但E64c一般抑制半胱氨酸蛋白酶，而CA074选择性地抑制半胱氨酸蛋白酶B。E64d最初用于肌营养不良症时被发现在临床上是安全的，但由于缺乏疗效而被停用。CA074被认为具有更安全的特征，因为它是组织蛋白酶B的特异性抑制剂，因此，E64c和CA074很可能是有效和安全的用于治疗AD。需要新的E64c和CA074前体药物来增加口服后的大脑浓度。这笔拨款将设计和合成两类新的此类前药，并在细胞和AD动物模型中对它们进行评估。第一个将是使E64c和CA074前药含有已知的酯，以增加亲脂性和增加脑渗透的可能性。另一种是E64c-和CA074-胡芦巴碱化合物，它通过将药物捕获在大脑中，同时促进其全身消除，从而增加大脑与系统的剂量比。口服前药的疗效将在正常和转基因AD动物模型中进行评估。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药物的翻译研究产生重大影响。公共卫生相关性：该项目与公共卫生相关。具体地说，该项目将开发新的有效的阿尔茨海默病药物。目前，没有有效的方法来阻止这种毁灭性疾病的进展，迫切需要能够做到这一点的新药。这一项目将产生可能阻止或可能逆转疾病发展的药物。因此，该项目具有巨大的潜力，可以改善数百万美国人及其家人的生活。

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.