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.

项目概要/摘要 阿尔茨海默病（AD）在神经病理学上被定义为由以下物质组成的细胞外斑块： β-淀粉样蛋白 (Aβ42) 和由过度磷酸化形式组成的细胞内缠结 微管相关蛋白 tau.Aβ 积累和 tau 过度磷酸化 被认为是全面发展 AD 神经病理学的关键事件。 优化一组独特的小分子药物，称为可溶性γ-分泌酶调节剂 (SGSMs) 进一步探索新的 AD 疗法。该提案将重点关注医学。 化学先导物优化和这些药物的功效测试旨在阻止 Aβ42- AD 转基因小鼠的相关病理学我们的总体假设是 SGSM 治疗的目标。 破坏 Aβ42 的产生将是前驱或早期的有效治疗方法 AD 以及散发性迟发性 AD 该项目的目标是完成所有的任务。 必要的 IND 支持研究，并在非常有效且安全的 SGSM 上提交 IND。

项目成果

The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease.

GSM BPN-15606 作为阿尔茨海默病预防性治疗的潜在候选药物。

• 发表时间: 2020
• 作者: Prikhodko, Olga;Rynearson, Kevin D;Sekhon, Travis;Mante, Mike M;Nguyen, Phuong D;Rissman, Robert A;Tanzi, Rudolph E;Wagner, Steven L
• 通讯作者: Wagner, Steven L