Optimization of Soluble Gamma-secretase Modulators for the Treatment of Alzheimer

用于治疗阿尔茨海默氏症的可溶性γ分泌酶调节剂的优化

基本信息

批准号：
8128185
负责人：
Steven Lee Wagner
金额：
$ 24.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128185
关键词：
Acetylcholinesterase Inhibitors Acute Affect Age Alzheimer&apos s Disease Amino Acids Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Behavioral Bioavailable Biochemical Biological Testing Brain Brain region Caregivers Cerebrum Chemical Structure Chronic Clinical Development Diffuse Disease Disease Progression Dose Drug Formulations Elderly Family member Funding Goals Healthcare Systems Human In Vitro Investigational Drugs Lead Learning Left Mediating Memory Molecular Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oral Administration Parents Pathogenesis Patients Peptides Pharmaceutical Chemistry Pharmacologic Substance Phase Plasma Preclinical Testing Process Prodrugs Production Property Proteolytic Processing Reagent Regimen Research Senile Plaques Series Site Societies Solubility Structure-Activity Relationship Testing Therapeutic Toxic effect Transgenic Animals Transgenic Mice Work aging population analog aqueous base gamma secretase improved meetings mouse model notch protein novel pre-clinical preclinical study prevent receptor secretase

项目摘要

DESCRIPTION (provided by applicant): The broad goals of our project are to pharmacologically optimize, mechanistically characterize (in the most appropriate molecular, cellular and transgenic animal models) and complete the entire preclinical development (through IND filing) of a potent orally bioavailable therapeutic compound carefully selected from a novel series of recently discovered gamma-secretase modulators (GSMs) for the treatment of Alzheimer's disease (AD). AD is neurodegenerative disorder that affects regions of the brain associated with learning and memory. AD affects over 24 million people world-wide and is an enormous burden to society. The extent at which it will affect our aging population will continue to escalate. A recently discovered a series of aryl 2-aminothiazole gamma-secretase modulators (AGSMs) that are pharmaceutical-like small organic molecules that are able to lower Abeta42 production without measurably affecting -Secretase-mediated enzymatic processing of other known gamma-secretase substrates such as the Notch-1 receptor. This project will focus on the pharmacological optimization of a series of AGSMs with improved physicochemical properties known as SGSMs. If successful in a number of predictive preclinical studies, these molecules will undergo further IND-enabling preclinical development and ultimately be tested in humans. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a major neurodegenerative disease that affects over 24 million people world-wide and currently there is no known cure. This disease if left without an appropriate intervening therapeutic will devastate our Healthcare systems.

描述（由申请人提供）：我们项目的广泛目标是在药理学优化的，机械方面的特征（在最合适的分子，细胞和转基因动物模型中），并完成整个临床上的开发（通过IND归档），以效果，可仔细地选择了来自最近发现的新型gama-secretishise ats for sms（gsme）（gsme）（gss）（gss）（gss）（gss）（gsme）（gss）（gsme）（gsme）（gss）。 AD是神经退行性疾病，影响与学习和记忆有关的大脑区域。广告在全球范围内影响超过2400万人，这给社会带来了巨大的负担。它将影响我们老龄化人口的程度将继续升级。最近发现了一系列芳基2-氨基硫唑γ-分泌酶调节剂（AGSM），它们是药物样的类小有机分子，能够降低Abeta42的产生，而无需测量 - 分泌酶介导的 - 分泌酶介导的酶介导的酶促处理其他已知的γ-凝集酶蛋白酶蛋白酶的酶促处理，例如Notch-notch-1。该项目将重点介绍一系列AGSM的药理学优化，具有改进的理化特性，称为SGSM。如果在许多预测临床前研究中成功，这些分子将经历进一步的临床前发展，并最终在人类中进行测试。公共卫生相关性：阿尔茨海默氏病是一种主要的神经退行性疾病，在全球范围内影响超过2400万人，目前尚无已知治愈方法。如果没有适当的中间治疗，则这种疾病将毁灭我们的医疗保健系统。