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-猫眼课题宝

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

批准号：

8605993

负责人：

Steven Lee Wagner

金额：

$7.48万

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

项目状态：

已结题

起止时间：

2011-07-01 至 2016-06-30

来源：

https://reporter.nih.gov/project-details/8605993

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

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中文摘要

翻译

描述(由申请人提供)：我们项目的广泛目标是优化药理，(在最合适的分子、细胞和转基因动物模型中)和完成有效的口服生物可用治疗化合物的整个临床前开发(通过IND备案)，该化合物是从最近发现的用于治疗阿尔茨海默病(AD)的一系列新颖的伽马分泌酶调节剂(GSM)中精心挑选出来的。AD是一种神经退行性疾病，影响大脑中与学习和记忆相关的区域。广告影响着全球2400多万人，给社会带来了巨大的负担。它对我们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-氨基噻唑伽玛分泌酶调节剂(AGSM)，它们是类似药物的小分子有机分子，能够降低Abeta42的产量，而不会显著影响分泌酶介导的其他已知伽玛分泌酶底物的酶处理，如Notch-1受体。该项目将专注于一系列具有改进的物理化学性质的AGSM的药理优化，即SGSM。如果在一些预测性的临床前研究中取得成功，这些分子将进行进一步的IND临床前开发，并最终在人体上进行测试。

英文摘要

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.

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