Development of E64d for Alzheimer's disease

开发用于治疗阿尔茨海默病的 E64d

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：目前尚无可用的药物来阻止阿尔茨海默氏病（AD）的进展。神经毒性脑SS-淀粉样蛋白肽的异常积累（A？）被认为是可能的一种疾病。一个？是由蛋白酶通过蛋白酶的蛋白水解裂解产生的，称为？ - 和？分泌酶。抑制2-分泌酶的裂解是减少A的有吸引力的方法吗？积累和？ - 分泌酶抑制剂被认为有效地有效地减缓了疾病的发展。我们发现了一个化合物E64D，可以改善空间记忆缺陷并减少脑斑块，a？和CTF？在脑室内（ICV）时，在转基因AD小鼠中。此外，E64D还减少了大脑A吗？在人类豚鼠模型中的受调节分泌途径中？生产。 CTF的减少？还有？在受调节的分泌途径中表明，E64D可以通过抑制该途径中的分泌酶活性来起作用。以前，其他人发现口服E64D给药可安全用于临床试验。因此，E64D在AD动物模型中既有效，又可以安全地用于人类，因此具有AD治疗的潜力。 E64D是其生物活性酸形式E64C的酯前药，它是半胱氨酸蛋白酶的特定抑制剂。 E64D在体内迅速水解为E64C。但是，ICV E64D给药不是一种治疗途径，口服E64D给药会导致脑剂量低，这是由于肝E64C在到达大脑之前的吸收。为了将E64D作为AD治疗，需要开发在治疗上可接受和有效的途径。该赠款将探索E64D给药的各种途径，并确定其在AD动物模型中的功效和脑剂量反应。如果找到合适的路线，这项工作将允许进行非常有前途的AD治疗性的临床开发。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氏病药物。当前，没有有效的方法可以阻止这种毁灭性疾病的进展，并且迫切需要这样做的新药。该项目可能会导致新的阿尔茨海默氏病治疗，可能会停止或可能扭转疾病的进展。