Novel Mechanisms of NSAID Action in Alzheimer's Disease

NSAID 治疗阿尔茨海默病的新机制

• 批准号: 6606278
• 负责人: EDWARD H. KOO
• 金额: $ 13.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606278
• 关键词: Alzheimer's disease; amyloid proteins; brain disorder chemotherapy; chemoprevention; neuropharmacology; nonsteroidal antiinflammatory agent

DESCRIPTION (provided by applicant): We have recently found that some non-steroidal anti-inflammatory drugs (NSAIDs) selectively decrease A?42 production by a mechanism that is independent of cyclooxygenase (COX) inhibition. Moreover, an independent study showed that chronic treatment with ibuprofen reduced A? deposition in a transgenic Alzheimer's disease (AD) mouse model. These data suggest that certain NSAIDs selectively reduce A?42, and that this effect rather than the COX mediated anti-inflammatory properties of these compounds might account for their apparent efficacy in reducing risk for AD. In order to explore this hypothesis the synthesis of novel compounds lacking COX activity yet maintaining the ability to lower A?42 is necessary. We have already identified several compounds that lack COX activity, lower A?42, and do so more potently than any of the FDA-approved NSAIDs. Moreover, we have identified a number of NSAID derivatives that unexpectedly raise A?42 and lower shorter A? derivatives including A?38. In addition, we have evidence that NSAIDs directly modulate gamma-secretase cleavage; therefore, we have begun to develop affinity reagents to identify the target responsible for the A?42 altering properties of these compounds. Finally, through systematic modification of several NSAIDs we have begun to identify important structure activity relationships (SAR) that are likely to result in the development of more potent and more selective A?42 lower agents. Based on these findings the aims of the chemical synthesis core are: 1) To produce large quantities of A?42 altering agents that are needed to conduct in vitro and in vivo studies outlined in Projects 1 and 2. 2) To synthesize affinity reagents derived from the A?42 altering agents that we have identified that can be used to identify the target responsible for the A?42 lowering effect of these compounds (Project 1). 3) To synthesize a series of molecules that will provide important information regarding the SAR of the A?42 altering agents. 4) Develop methods to enable detection and quantification of the level of these novel compounds in biological fluids and tissues.

描述(申请人提供)：我们最近发现一些非类固醇抗炎药(NSAIDs)选择性地减少A？42的产生，其机制与环氧合酶(COX)抑制无关。此外，一项独立研究表明，布洛芬慢性治疗会降低A？在转基因阿尔茨海默病(AD)小鼠模型中的沉积。这些数据表明，某些非甾体抗炎药选择性地降低A42，这种作用而不是这些化合物的COX介导的抗炎特性可能解释了它们在降低AD风险方面的明显效果。为了探索这一假说，合成缺乏COX活性但保持降低A？42能力的新化合物是必要的。 我们已经确定了几种缺乏COX活性的化合物，A？42较低，而且作用更强。 比FDA批准的任何非类固醇抗炎药都有效。此外，我们还确认了一些非甾体抗炎药 衍生品出人意料地上涨了42澳元，并降低了做空A？衍生品包括38澳元。在……里面 此外，我们有证据表明，非甾体抗炎药直接调节伽马分泌酶的切割；因此，我们已经开始开发亲和试剂来识别导致这些化合物A？42改变性质的靶点。最后，通过对几种非甾体抗炎药的系统修饰，我们已经开始确定重要的结构活性关系(SAR)，这些关系可能导致开发更有效和更具选择性的A？42降解剂。基于这些发现，化学合成核心的目标是：1)生产进行项目1和2中概述的体外和体内研究所需的大量A？42调节剂。2)合成从我们已确定的A？42调节剂衍生的亲和剂，这些试剂可用于确定这些化合物降低A？42效应的靶点(项目1)。3)合成一系列分子，为A？42改性剂的SAR提供重要信息。4)开发能够检测和量化生物液和组织中这些新化合物水平的方法。