Development of E64d for Alzheimer's disease

开发用于治疗阿尔茨海默病的 E64d

• 批准号: 7541167
• 负责人: GREGORY R HOOK
• 金额: $ 11.51万
• 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: 2008-09-30 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541167
• 关键词: Acids; Active Sites; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Experiments; Animal Model; Animals; Asses; Behavior; Binding; Biological Availability; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Bos taurus; Brain; Carotid Arteries; Cathepsins B; Cattle; Cavia; Child; Chromaffin Cells; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Collaborations; Cyclodextrins; Cysteine Protease; Cysteine Proteinase Inhibitors; Data; Development; Dimethyl Sulfoxide; Disease; Disease Progression; Dose; Double-Blind Method; Drug Formulations; Drug Kinetics; E 64c; Endopeptidases; Esters; Evaluation; Excipients; Expressed Sequence Tags; Funding; Goals; Government; Grant; Health; Hepatic; Housing; Human; Hydrolysis; Infusion procedures; Injection of therapeutic agent; Intravenous; Japan; Japanese Population; Journals; Kidney; Label; Liver; London; Measures; Memory impairment; Modeling; Monkeys; Mus; Muscular Dystrophies; Mutation; Nose; Numbers; Oral; Oral Administration; Other Finding; Paper; Pathology; Pathway interactions; Patients; Penetration; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Procedures; Prodrugs; Production; Public Health; Publishing; Purpose; Range; Research; Route; Secretory Vesicles; Senile Plaques; Site; Social Welfare; Solutions; Sulfhydryl Compounds; Testing; Therapeutic; Thinking; Tissues; Toxicology; Transgenic Mice; Transgenic Organisms; Translating; Work; amyloid peptide; base; cost; cost effective; day; improved; in vivo; inhibitor/antagonist; male; morris water maze; mouse model; neurotoxic; peptide A; pre-clinical; programs; research study; response; secretase; transgenic model of alzheimer disease; uptake; volunteer; young adult

DESCRIPTION (provided by applicant): There currently is no drug available that stops the progression of Alzheimer's disease (AD). The abnormal accumulation of neurotoxic brain ss-amyloid peptides (A?) is thought to be a possible cause the disease. A? are produced by proteolytic cleavage of a larger amyloid precursor protein by proteases, called ?- and ?-secretases. Inhibiting 2-secretase cleavage is an attractive approach to reducing A? accumulation and ?-secretase inhibitors are thought to potentially effective for slowing the progression of the disease. We have found a compound, E64d, which improves spatial memory deficit and reduces brain plaque, A? and CTF? in a transgenic AD mouse when intracerebroventricularly (icv) administered. Moreover, E64d also reduces brain A? in the regulated secretory pathway in the guinea pig model of human A? production. The reduction in CTF? and A? in the regulated secretory pathway suggests that E64d may act by inhibiting ?-secretase activity in that pathway. Previously, others found that oral E64d administration safe to use in clinical trials. Thus, E64d is both efficacious in AD animal models and safe to use in humans and therefore has potential as an AD therapeutic. E64d is an ester prodrug of its biologically active acid form, E64c, which is a specific inhibitor of cysteine proteases. E64d is rapidly hydrolyzed to E64c in vivo. However, icv E64d administration is not a therapeutically acceptable route and oral E64d administration results in low brain doses, which is due to hepatic E64c uptake prior to reaching the brain. Therapeutically acceptable and efficacious routes of E64d administration need to be developed in order to advance E64d as an AD therapeutic. This grant will explore various routes of E64d administration and determine their efficacy and brain dose responses in AD animal models. If a suitable route is found, this work will allow the clinical development of a very promising AD therapeutic to proceed. PUBLIC HEALTH RELEVANCE: The relevance of this project to the public health is the development of new and effective Alzheimer's disease drug. 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 a new Alzheimer's disease treatment that may halt or, possibly, reverse the progression of the disease.

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。神经毒性脑β-淀粉样肽（A？）被认为是导致这种疾病的可能原因。一个？是由蛋白酶对较大的淀粉样前体蛋白进行蛋白水解裂解而产生的，称为？然后呢？分泌酶抑制2-分泌酶切割是减少A？积累和？分泌酶抑制剂被认为对减缓疾病的进展是潜在有效的。我们已经发现了一种化合物，E64 d，它可以改善空间记忆缺陷，减少大脑斑块，A？而CTF？在转基因AD小鼠脑室内（icv）给药时。此外，E64 d还降低脑A？在豚鼠模型的人A？生产CTF的减少？而A？在调节分泌途径中的作用表明E64 d可能通过抑制？分泌酶活性。以前，其他人发现口服E64 d在临床试验中使用是安全的。因此，E64 d在AD动物模型中是有效的，并且在人类中使用是安全的，因此具有作为AD治疗剂的潜力。E64 d是其生物活性酸形式E64 c的酯前药，E64 c是半胱氨酸蛋白酶的特异性抑制剂。E64 d在体内迅速水解为E64 c。然而，icv E64 d给药不是治疗上可接受的途径，口服E64 d给药导致脑剂量低，这是由于E64 c在到达脑之前被肝脏摄取。需要开发治疗上可接受且有效的E64 d给药途径，以推进E64 d作为AD治疗剂。该基金将探索E64 d给药的各种途径，并确定其在AD动物模型中的疗效和脑剂量反应。如果找到合适的途径，这项工作将使一种非常有前途的AD治疗药物的临床开发得以进行。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病药物。目前，还没有有效的手段来阻止这种毁灭性疾病的进展，迫切需要新的药物。该项目可能会导致一种新的阿尔茨海默病治疗方法，可能会阻止或逆转疾病的进展。