AD 可溶性 γ 分泌酶调节剂的优化和临床前开发-猫眼课题宝

AD 可溶性 γ 分泌酶调节剂的优化和临床前开发

批准号：

9913370

负责人：

Steven Lee Wagner

金额：

$39.38万

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：

2016

资助国家：

美国

项目状态：

已结题

起止时间：

2016-05-15 至 2020-04-30

来源：

https://reporter.nih.gov/project-details/9913370

关键词：

Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Award Behavioral Binding Proteins Biochemical Biological Assay Biological Availability Brain Cerebrospinal Fluid Cerebrum Chemicals Chemistry Chromosome abnormality Chronic Cognitive Data Disease Dose Economic Burden Enzyme Inhibition Enzyme Inhibitor Drugs Event Evolution Exhibits Family Goals Health Health Expenditures Human In Vitro Late Onset Alzheimer Disease Lead Ligands Link Liver Extract MAPT gene Metabolic Micronucleus Tests Mus Mutation Neurofibrillary Tangles Oral Oral Administration Palliative Care Pathogenesis Pathogenicity Pathologic Pathology Penetrance Peptides Pharmaceutical Preparations Pharmacology Phenotype Plasma Plasma Proteins Preparation Production Property Pyridazines Quantitative Structure-Activity Relationship Rattus Regimen Salmonella Senile Plaques Source Structure Structure-Activity Relationship Therapeutic Transgenic Mice abeta accumulation analog attenuation base beta-site APP cleaving enzyme 1 clinical candidate clinical development drug testing effective therapy efficacy testing extracellular familial Alzheimer disease gamma secretase improved in vivo inhibitor/antagonist lead optimization meetings member mouse model neuropathology novel peptide I pre-clinical preclinical development prevent programs scaffold secretase side effect small molecule social stigma tau Proteins

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英文摘要

Project Summary/Abstract Alzheimer's Disease (AD) is defined neuropathologically by extracellular plaques composed of β-amyloid (Aβ42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau.Aβ accumulation and hyperphosphorylation of tau are recognized as key eventsl eading to full blown AD neuropathology. Here we propose to further optimize a unique set of small molecule drugs known as soluble gamma-secretase modulators (SGSMs) to further explore novel AD therapeutics. This proposal will focus on the medicnal chemistry lead optimization and the testing of the efficacy of these drugs aimed at halting Aβ42- related pathologies in AD transgenic mice. Our overarching hypothesis is SGSM therapy aimed to disrupt production of Aβ42 will be an efficacious treatment approach for prodromal or early AD as well as sporadic late-onset AD. The goal of this project is to complete all of the necessary IND-enabling studies and to file an IND on a very potent and safe SGSM.

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