Development of protease inhibitor drugs to treat Alzheimer's disease

开发治疗阿尔茨海默病的蛋白酶抑制剂药物

• 批准号: 7743874
• 负责人: GREGORY R HOOK
• 金额: $ 42.75万
• 依托单位: AMERICAN LIFE SCIENCE PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743874
• 关键词: Aldehydes; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Animal Model; Animals; Anus; Asses; Behavior; Binding; Bioavailable; Biological Assay; Blood - brain barrier anatomy; Brain; Cathepsins B; Cavia; Cells; Chronic; Cleaved cell; Clinical Treatment; Cysteine Protease; Cysteine Proteinase Inhibitors; Data; Defect; Development; Dipeptides; Disease; Disease Progression; Dose; Esters; Expressed Sequence Tags; Goals; Grant; Hand; Histology; Human; In Vitro; Inhibitory Concentration 50; Kidney; Lead; Libraries; Liver; Liver diseases; London; Memory; Memory impairment; Methods; Modeling; Mutant Strains Mice; Mutate; Neurologic; Neurons; Oral Administration; Pathology; Pathway interactions; Patients; Penetration; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Population; Process; Prodrugs; Production; Protease Inhibitor; Public Health; Publishing; Recombinants; Risk; Route; Screening procedure; Secretory Vesicles; Site; Supervision; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Transgenic Mice; Transgenic Organisms; Weight; Work; amyloid peptide; chemical synthesis; design; drug development; effective therapy; improved; in vitro Assay; in vivo; inhibitor/antagonist; morris water maze; mouse model; mutant; mutant mouse model; neurotoxic; peptide structure; peptidomimetics; preference; secretase; small molecule

DESCRIPTION (provided by applicant): There currently is no drug available that stops the progression of Alzheimer's disease (AD). Neurotoxic ?-amyloid peptides (A??) are thought to cause the disease with their accumulation in brain plaques being a hallmark. A? are cleaved from a larger amyloid precursor protein (APP) by proteases, called ?? and ?-secretases. Compounds that inhibit ?-secretase may stop the progression of the disease by reducing the production of A?. CA074Me and loxistatin (also known as E64d or EST) are cysteine protease inhibitors and the cysteine protease, cathepsin B, is a candidate 2-secretase in the regulated secretory pathway. The inhibiton of brain 2-secretase by these compounds is likely due to inhibition of cathepsin B ? -secretase activity. Although loxistatin has been shown safe to use in humans, non-specific binding by this compound, and the structurally similar CA074Me, may limit their therapeutic use. Reversible protease inhibitors offer potential pharmacological advantages as AD therapeutics. This grant, therefore, will develop reversible, small molecule, cathepsin B inhibitors and determine their efficacy in various AD models. Published data show that the reversible peptidomimetic cathepsin B inhibitor, Ac-LVK-CHO, reduces brain A? and brain ?-secretase activity in the guinea pig model, making it likely that the reversible cathepsin B inhibitors developed in this grant will be efficacious. If successful, the work will usher in a new class of AD therapeutics that could have a major impact on treating this dreadful disease. PUBLIC HEALTH RELEVANCE: The relevance of this project to the public health is the development of 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 may result in drugs that halt or, possibly, reverse the progression of AD.

描述（由申请人提供）：目前尚无可用的药物来阻止阿尔茨海默氏病（AD）的进展。神经毒性？ - 淀粉样蛋白肽（A ??）被认为会导致该疾病，因为它们在脑斑块中的积累是标志。一个？是否会被称为蛋白酶从较大的淀粉样前体蛋白（APP）中裂开，称为？和？ - 分泌酶。抑制？ - 分泌酶的化合物可以通过减少A？的产生来阻止疾病的进展。 CA074ME和Loxistatin（也称为E64D或EST）是半胱氨酸蛋白酶抑制剂，半胱氨酸蛋白酶calterpsin b是调节分泌途径中的候选2-分泌酶。这些化合物对大脑2-分泌酶的抑制剂可能是由于组织蛋白酶B的抑制作用吗？ - 分泌酶活性。尽管已证明了洛克天蛋白在人类中安全使用，但该化合物的非特异性结合，结构相似的Ca074me可能会限制其治疗用途。 可逆蛋白酶抑制剂可作为AD治疗药物提供潜在的药理优势。因此，该赠款将产生可逆的小分子，组织蛋白酶B抑制剂，并在各种AD模型中确定其功效。已发表的数据表明，可逆的肽瘤组织蛋白酶B抑制剂AC-LVK-CHO可减少大脑A？和大脑？ - 豚鼠模型中的分泌酶活性，使得本赠款中开发的可逆组织蛋白酶B抑制剂可能会有效。如果成功的话，这项工作将引入新的广告疗法，这可能会对治疗这种可怕的疾病产生重大影响。公共卫生相关性：该项目与公共卫生的相关性是开发新的有效的阿尔茨海默氏病药物。当前，没有有效的方法可以阻止这种毁灭性疾病的进展，并且迫切需要这样做的新药。该项目可能导致停止或可能扭转AD进展的药物。