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.

SBIR 快速通道资助项目：用于阿尔茨海默病的蛋白酶抑制剂 以下标有星号 (*) 的部分包含专有信息 ALSP, Inc. 要求不得向政府以外的人员透露信息，除非 审查和评价的目的。 抽象的 目前尚无药物可以阻止阿尔茨海默病的进展 （广告）。神经毒性 ss-淀粉样肽 (Ass) 被认为是导致这种疾病的原因 脑斑块中的积累是一个标志。屁股是从较大的淀粉样蛋白上切下来的 前体蛋白 (APP) 由蛋白酶（称为 ¿- 和 ¿-分泌酶）产生。化合物 抑制 ¿-分泌酶可以通过减少产量来阻止疾病的进展 A¿。 *初步数据显示，蛋白酶抑制剂 CA074Me 和洛西他汀， *显着改善转基因 AD 小鼠的行为和病理学 *模型，导致记忆缺陷显着改善，显着 *脑斑减少，脑屁股减少 50%，以及类似的减少 *脑 ¿-分泌酶活性。此外，已发表的数据表明这些抑制剂 *还降低受调节分泌途径中的大脑 Ass 和 ¿-分泌酶活性 *在人类 A¿ 处理的非转基因豚鼠模型中减少 50-60%。这 *这些化合物在与 AD 药物相关的两种动物模型中有效的事实 *开发强烈表明它们作为 AD 疗法的潜力。 CA074Me 和洛西他汀（也称为 E64d 或 EST）是半胱氨酸蛋白酶抑制剂 半胱氨酸蛋白酶组织蛋白酶 B 是受调控的 ¿-分泌酶的候选酶 分泌途径。这些化合物对脑 β-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是安全的 用于人类，该化合物的非特异性结合，以及结构相似 CA074Me，可能会限制其治疗用途。 可逆性蛋白酶抑制剂作为 AD 具有潜在的药理学优势 疗法。因此，这笔资助将开发可逆的小分子组织蛋白酶 B 抑制剂并确定其在各种 AD 模型中的功效。公布的数据显示 可逆的拟肽组织蛋白酶 B 抑制剂 Ac-LVK-CHO 可减少脑 A¿ 豚鼠模型中的脑 ¿-分泌酶活性，使得可逆的 本次资助开发的组织蛋白酶 B 抑制剂将是有效的。如果成功的话，工作 将迎来一类新的 AD 疗法，可能对治疗产生重大影响 这种可怕的疾病。