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.

Fast-Track SBIR赠款标题为：阿尔茨海默氏症的蛋白酶抑制剂 标记标有星号（*）的以下部分包含专有信息 ALSP，Inc。的请求未向政府以外的人发布，除了 审查和评估的目的。 抽象的 目前尚无药物阻止阿尔茨海默氏病的进展 （广告）。神经毒性SS-淀粉样蛋白肽（AS）被认为引起疾病 在脑斑块中积累是一个标志。屁股从较大的淀粉样蛋白裂开 蛋白酶的前体蛋白（APP）称为�-和€ - 分泌酶。复合 抑制 - 分泌酶可能通过减少生产来阻止疾病的进展 a。 *初步数据表明，蛋白酶抑制剂Ca074me和loxistatin， *显着改善转基因AD鼠标的行为和病理 *模型，导致记忆不足的显着改善，这是一个戏剧性的 *减少脑牌匾，减少50％的脑屁股和类似的降低 *脑�-分泌酶活性。此外，已发布的数据表明这些抑制剂 *还会减少脑屁股和 - 分泌酶的活性 *在人类a处理的非转基因豚鼠模型中，乘以50-60％。这 *这些化合物在与AD药物有关的两个动物模型中有效 *发展强烈暗示了它们作为广告疗法的潜力。 CA074ME和Loxistatin（也称为E64D或EST）是半胱氨酸蛋白抑制剂 半胱氨酸蛋白Bstepsin B是调节中的候选„ - 分泌酶 秘密途径。这些化合物的大脑抑制剂»溶解酶可能是由于 抑制组织蛋白酶b。 - 分泌酶活性。尽管已证明洛克天蛋白已经安全 用于人类，该化合物的非特异性结合，结构相似 CA074ME，可能会限制其治疗用途。 可逆蛋白酶抑制剂可作为广告提供潜在的药物优势 疗法。因此，该赠款将发展可逆的小分子，组织蛋白酶B 抑制剂并确定其在各种AD模型中的效率。已发布的数据显示 可逆肽模拟组织蛋白酶B抑制剂AC-LVK-CHO可减少大脑A a。 大脑�-豚鼠模型中的分泌酶活性，使得可逆 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，工作 会迎来一类新的广告疗法，可能会对治疗产生重大影响 这种可怕的疾病。