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: 7477514
• 负责人: GREGORY R HOOK
• 金额: $ 9.51万
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477514
• 关键词: Aldehydes; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Animals; Anus; Behavior; Binding; Bioavailable; Biological Assay; Blood - brain barrier anatomy; Brain; CA 074 methyl ester; Cathepsins B; Cavia; Cells; Chronic; Class; Cleaved cell; Clinical Treatment; Clinical Trials; Cysteine Protease; Cysteine Proteinase Inhibitors; Data; Defect; Development; Dipeptides; Disease; Disease Progression; Dose; E 64c; Endopeptidases; 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; Population; Process; Prodrugs; Production; Protease Inhibitor; Public Health; Publishing; Recombinants; Risk; Route; Screening procedure; Secretory Vesicles; Site; Supervision; Testing; Therapeutic; Therapeutic Uses; Thinking; Toxic effect; Transgenic Mice; Transgenic Organisms; Weight; Work; amyloid peptide; chemical synthesis; day; design; drug development; improved; in vitro Assay; in vivo; inhibitor/antagonist; morris water maze; mouse model; mutant; mutant mouse model; neurotoxic; peptide A; 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）：目前还没有药物可以阻止阿尔茨海默病（AD）的进展。神经毒性β-淀粉样肽（A??）被认为是导致这种疾病的原因，其标志是它们在脑斑块中的积累。一个？被称为 ?? 的蛋白酶从较大的淀粉样前体蛋白 (APP) 上切割下来。和β-分泌酶。抑制β-分泌酶的化合物可以通过减少Aβ的产生来阻止疾病的进展。 CA074Me 和洛西他汀（也称为 E64d 或 EST）是半胱氨酸蛋白酶抑制剂，而半胱氨酸蛋白酶组织蛋白酶 B 是调节分泌途径中的候选 2-分泌酶。这些化合物对脑 2-分泌酶的抑制可能是由于抑制组织蛋白酶 B ? -分泌酶活性。尽管洛西他汀已被证明可安全用于人类，但该化合物的非特异性结合以及结构相似的 CA074Me 可能会限制其治疗用途。 可逆蛋白酶抑制剂作为 AD 疗法具有潜在的药理学优势。因此，这笔资金将开发可逆的小分子组织蛋白酶 B 抑制剂，并确定它们在各种 AD 模型中的功效。已发表的数据表明，可逆的拟肽组织蛋白酶 B 抑制剂 Ac-LVK-CHO 可降低脑 A?以及豚鼠模型中大脑 β-分泌酶活性的结果，使得本次资助中开发的可逆组织蛋白酶 B 抑制剂很可能有效。如果成功，这项工作将带来一类新的 AD 疗法，可能对治疗这种可怕的疾病产生重大影响。公共健康相关性：该项目与公共健康的相关性是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。该项目可能会产生能够阻止或逆转 AD 进展的药物。