Development of E64d for Alzheimer's disease

开发用于治疗阿尔茨海默病的 E64d

• 批准号: 7767386
• 负责人: GREGORY R HOOK
• 金额: $ 56.72万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767386
• 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; 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; Esters; Evaluation; Excipients; Expressed Sequence Tags; Funding; Goals; 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; Oral; Oral Administration; Paper; Pathology; Pathway interactions; Patients; Penetration; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Procedures; Prodrugs; Production; Public Health; Publishing; Research; Route; Secretory Vesicles; Senile Plaques; Site; Social Welfare; Solutions; Sulfhydryl Compounds; Testing; Therapeutic; Tissues; Toxicology; Transgenic Mice; Transgenic Organisms; Translating; Work; amyloid peptide; base; cost; improved; in vivo; inhibitor/antagonist; male; morris water maze; mouse model; neurotoxic; 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(申请人提供)：目前还没有阻止阿尔茨海默病(AD)进展的药物。神经毒性脑内淀粉样多肽(A？)被认为是这种疾病的可能原因。一个?是由一种更大的淀粉样前体蛋白被称为？-和？-分泌酶的蛋白水解酶产生的。抑制2-分泌酶的切割是降低A？积聚和β-分泌酶抑制剂被认为可能有效地减缓疾病的进展。我们已经发现了一种化合物，E64d，它可以改善空间记忆缺陷，减少脑斑块，A？那CTF呢？在转基因AD小鼠中，脑室注射(Icv)。此外，E64d还降低了脑A？在人A？的豚鼠模型中？制作。CTF的降低？那A呢？提示E64d可能通过抑制该途径中的β-分泌酶活性发挥作用。此前，其他人发现在临床试验中使用口服E64d是安全的。因此，E64d在AD动物模型中是有效的，在人类中使用也是安全的，因此具有治疗AD的潜力。E64d是一种具有生物活性的酸形式的酯类前药，E64c是半胱氨酸蛋白酶的特异性抑制剂。在体内，E64d迅速被水解为E64c。然而，icv E64d给药在治疗上是不可接受的，口服E64d会导致低脑剂量，这是由于肝脏在E64c到达大脑之前摄取。为了促进E64d作为AD的治疗手段，需要开发治疗上可接受和有效的E64d给药途径。这笔赠款将探索E64d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。如果找到一条合适的路线，这项工作将使非常有希望的AD疗法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，没有有效的方法来阻止这种毁灭性疾病的进展，迫切需要能够做到这一点的新药。这一项目可能会导致一种新的阿尔茨海默病治疗方法，可能会阻止或可能逆转疾病的发展。