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: 7935012
• 负责人: GREGORY R HOOK
• 金额: $ 19.6万
• 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: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935012
• 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; Evaluation; Expressed Sequence Tags; Goals; Government; 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; Persons; 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; Small Business Innovation Research Grant; Supervision; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Transgenic Mice; Transgenic Organisms; Weight; Work; abstracting; 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

Fast-Track SBIR Grant Entitled: Protease Inhibitors for Alzheimer's The following sections marked with an asterisk (*) contain proprietary information that ALSP, Inc. requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract There currently is no drug available that stops the progression of Alzheimer's disease (AD). Neurotoxic ss-amyloid peptides (Ass) are thought to cause the disease with their accumulation in brain plaques being a hallmark. Ass 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¿. *Preliminary data show that the protease inhibitors, CA074Me and loxistatin, *dramatically improve the behavior and pathology in a transgenic AD mouse *model, causing a significant improvement in memory deficit, a dramatic *reduction in brain plaque, a 50% reduction in brain Ass and a similar reduction in *brain ¿-secretase activity. Moreover, published data shows that these inhibitors *also reduce brain Ass and ¿-secretase activity in the regulated secretory pathway *by 50-60% in the non-transgenic guinea pig model of human A¿ processing. The *fact that these compounds are effective in two animal models relevant to AD drug *development strongly suggests their potential as AD therapeutics. CA074Me and loxistatin (also known as E64d or EST) are cysteine protease inhibitors and the cysteine protease, cathepsin B, is a candidate ¿-secretase in the regulated secretory pathway. The inhibiton of brain ¿-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.

快速通道SBIR赠款题为：治疗阿尔茨海默氏症的蛋白酶抑制剂 标有星号(*)的下列部分包含专有信息 ALSP，Inc.的请求不得向政府以外的人发布，但以下情况除外 审查和评估的目的。 摘要 目前还没有可以阻止阿尔茨海默病进展的药物 (Ad)。神经毒性淀粉样多肽(Ass)被认为是通过它们的 大脑斑块的堆积是一个标志。驴是从较大的淀粉样蛋白中分离出来的 前体蛋白(APP)由蛋白酶产生，称为分泌酶和分泌酶。一种化合物 抑制分泌酶可能通过减少产量来阻止疾病的进展。 A？的。 *初步数据显示，蛋白酶抑制剂CA074Me和loxistatin， *显著改善转基因AD小鼠的行为和病理 *模型，导致记忆缺陷显著改善，戏剧性 *减少脑斑块，减少50%的大脑ASS和类似的减少 *大脑--分泌酶活性。此外，公布的数据显示，这些抑制剂 *还会降低受调节的分泌途径中的脑ASS和分泌酶活性 *在人A？处理的非转基因豚鼠模型中增加50%-60%。这个 *这些化合物在两个与AD药物相关的动物模型中有效 *发展有力地表明了它们作为AD疗法的潜力。 CA074Me和loxistatin(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，是被调控的 分泌途径。这些化合物对脑分泌酶的抑制可能是由于 抑制组织蛋白酶B？分泌酶活性。尽管洛西他丁已被证明是安全的 在人体上使用时，这种化合物非特异性结合，与结构相似 CA074Me，可能会限制它们的治疗用途。 可逆酶抑制剂提供潜在的药理优势，如AD 治疗学。因此，这笔赠款将开发可逆的小分子组织蛋白酶B 并测定其在各种AD模型中的疗效。公布的数据显示， 可逆类肽类组织蛋白酶B抑制剂Ac-LVK-CHO可降低脑A和 豚鼠模型中脑分泌酶的活性，使其很可能是可逆的 在这笔赠款中开发的组织蛋白酶B抑制剂将是有效的。如果成功，这项工作 将迎来一类新的AD疗法，可能会对治疗产生重大影响 这种可怕的疾病。