Prodrugs to treat Alzheimer's disease

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，发生在老年人身上，导致记忆和认知过程丧失。全世界每年的AD费用估计为3154亿美元，这比世界上除8个国家外的所有国家的预算都要高。目前没有办法阻止阿尔茨海默病的发展。一个中心假设是β -淀粉样蛋白（A2）肽的异常积累导致大脑中负责记忆的区域的神经元变性。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。一个特别有吸引力的目标是2-分泌酶，它可以切割淀粉样蛋白前体蛋白（APP），产生A2的氨基末端。我们发现化合物E64d和CA074Me对表达含有野生型2-分泌酶位点的APP的AD动物模型有效，这在大多数AD患者中都存在。值得注意的是，我们发现E64d和CA074Me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了记忆，减少了脑淀粉样斑块，这是AD的两个特征。他们还减少了大脑A2和CTF2，这是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-分泌酶的活性起作用。E64d和CA074Me分别是其酸型E64c和CA074的乙基和甲酯前药，在体内具有活性。尽管结构非常相似，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，组织蛋白酶b。E64d最初用于治疗肌肉萎缩症时被发现临床安全，但由于缺乏疗效而停止使用。由于CA074是一种组织蛋白酶B特异性抑制剂，因此，E64c和CA074可能既有效又安全，可用于AD。需要新的E64c和CA074前药，以增加口服后的脑浓度。该基金将设计和合成两类新的此类前药，并在细胞和AD动物模型中进行评估。第一种方法是制造含有酯的E64c和CA074前药，这些酯可以增加亲脂性，增加大脑渗透的可能性。另一种是E64c-和ca074 -葫芦巴碱化合物，它们通过将药物困在大脑中，同时促进其全身消除，从而增加脑与全身的剂量比。将在正常和转基因AD动物模型中评估口服前药的效果。该项目有望通过引入一类全新的半胱氨酸蛋白酶抑制剂阿尔茨海默病药物，对阿尔茨海默病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发展，因此迫切需要能够阻止这种疾病的新药。这一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。

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.