Optimization and preclinical development of soluble gamma-secretase modulators for AD

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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913370
• 关键词: Alzheimer' s Disease; Alzheimer' 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

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.

项目总结/摘要 阿尔茨海默氏病（AD）在神经病理学上被定义为细胞外斑块， β-淀粉样蛋白（Aβ42）和由过度磷酸化形式的 微管相关蛋白tau。Aβ的积累和tau蛋白的过度磷酸化是 被认为是导致全面AD神经病理学的关键事件。在此，我们建议进一步 优化一套独特的小分子药物，称为可溶性γ-分泌酶调节剂， （SGSM），以进一步探索新的AD治疗方法。该提案将侧重于医学 化学导致优化和测试这些药物的有效性，旨在阻止Aβ42- AD转基因小鼠的相关病理学。我们的总体假设是SGSM治疗的目的是 干扰Aβ42的产生将是前驱或早期 AD以及散发性迟发性AD。该项目的目标是完成所有 必要的IND使能研究，并就非常有效和安全的SGSM提交IND。