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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：
8911866
负责人：
Steven Lee Wagner
金额：
$ 5.3万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911866
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.

描述（由申请人提供）：我们项目的总体目标是药理学优化，机制表征（在最合适的分子，细胞和转基因动物模型中）并完成整个临床前开发（通过IND申请），从最近发现的一系列新的γ分泌酶调节剂（gsm）中精心挑选出有效的口服生物可利用治疗化合物，用于治疗阿尔茨海默病（AD）。阿尔茨海默病是一种神经退行性疾病，影响大脑中与学习和记忆有关的区域。阿尔茨海默病影响着全世界2400多万人，是社会的巨大负担。它对我国老龄化人口的影响程度将继续升级。最近发现了一系列芳基2-氨基噻唑γ -分泌酶调节剂（AGSMs），它们是类似药物的小有机分子，能够降低Abeta42的产生，而不会明显影响-分泌酶介导的其他已知γ -分泌酶底物（如Notch-1受体）的酶处理。本项目将重点关注一系列具有改进的物理化学性质的AGSMs （SGSMs）的药理优化。如果在一些预测性临床前研究中取得成功，这些分子将进行进一步的临床前开发，并最终在人体中进行测试。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.

DOI：
10.1016/j.bmc.2020.115734
发表时间：
2020-11-15
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Rynearson KD;Buckle RN;Herr RJ;Mayhew NJ;Chen X;Paquette WD;Sakwa SA;Yang J;Barnes KD;Nguyen P;Mobley WC;Johnson G;Lin JH;Tanzi RE;Wagner SL
通讯作者：
Wagner SL