PKC Modulators for the Treatment of Alzheimer's disease

用于治疗阿尔茨海默病的 PKC 调节剂

• 批准号: 6966114
• 负责人: ALAN Paul KOZIKOWSKI
• 金额: $ 44.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966114
• 关键词: Alzheimer' s disease; amyloid proteins; aspartic endopeptidases; brain disorder chemotherapy; chemical models; computer simulation; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme induction /repression; genetically modified animals; laboratory mouse; lactams; presenilin; protease inhibitor; protein kinase C; protein metabolism; protein protein interaction; tau proteins

DESCRIPTION (provided by applicant): There is a growing consensus that the pivotal event in the pathophysiology of Alzheimer's disease (AD) is overproduction of amyloid beta peptide (Abeta). If this formulation is correct, then there are three primary strategies for interrupting the pathologic cascade: inhibiting beta-secretase, inhibiting gamma-secretase, or augmenting alpha-secretase. Intuitively, if Abeta is the culprit, reducing the generation of the peptide is the most promising approach. Both beta- and gamma-secretase are necessary for generation of intact Abeta, while alpha-secretase cleaves within the Abeta domain, preventing its release intact. The pharmaceutical industry has invested heavily in the development of beta- and gamma-secretase inhibitors, though none has yet succeeded in human trials. We propose a strategy based on the third approach, augmenting alpha-secretase activity. Our approach to augmenting alpha-secretase activity involves modulating protein kinase C (PKC), which has conclusively been linked to regulation of alpha-secretase in a number of laboratories. In this regard, we have shown recently that the structurally novel PKC activator, 8-(1-decynyl)-benzolactam, is able to reverse K+ channels defects and to enhance the production of the alpha-secretase product sAPPalpha in AD cells. More importantly, when tested in vivo, this benzolactam significantly increased the amount of sAPPalpha and reduced Abeta40 in the brains of APP[V7171] transgenic mice. Given the promising animal data achieved with the 8-(1-decynyl)-benzolactam and our long experience in the SAR of the benzolactams (BL), we propose to conduct a highly focused study aimed at defining the best benzolactam analog that can serve as a clinical candidate for the treatment of AD. To achieve this goal, our aims become the following: 1. Conduct both compound design using molecular modeling tools and the chemical synthesis of novel BLs with the aim to optimize effects on alpha-secretase activity while diminishing any possible tumor promoting activity; Much of this work will focus on altering the nature of the side chain appendages; 2. Carry out in vitro studies to define the biological activity of new analogs. Screen all compounds for activity as PKC activators. Test selected potent PKC activators (EC50 at least 50 nM) on levels of sAPPalpha and Abeta 1-40 and 1-42. Test compounds effective in enhancing sAPPalpha production for tumor promoting effects; 3. For the best compounds from Aim 2, perform studies in triple transgenic mice to ascertain effects on Abeta and sAPPalpha levels and plaque formation in vivo.

描述（由申请人提供）：越来越多的共识认为，阿尔茨海默病（AD）病理生理学的关键事件是淀粉样β肽（Abeta）的过量产生。如果这个表述是正确的，那么中断病理级联的三种主要策略是：抑制 β 分泌酶、抑制 γ 分泌酶或增强 α 分泌酶。直观上，如果 Abeta 是罪魁祸首，那么减少肽的产生是最有希望的方法。 β 和 γ 分泌酶都是生成完整 Abeta 所必需的，而 α 分泌酶会在 Abeta 结构域内裂解，从而阻止其完整释放。制药业在β-和γ-分泌酶抑制剂的开发上投入了大量资金，但尚未在人体试验中取得成功。我们提出了一种基于第三种方法的策略，即增强α-分泌酶活性。我们增强 α 分泌酶活性的方法涉及调节蛋白激酶 C (PKC)，许多实验室已证实它与 α 分泌酶的调节有关。在这方面，我们最近证明结构新颖的 PKC 激活剂 8-(1-癸炔基)-苯并内酰胺能够逆转 K+ 通道缺陷并增强 AD 细胞中 α 分泌酶产物 sAPPalpha 的产生。更重要的是，在体内测试时，这种苯并内酰胺显着增加了 APP[V7171] 转基因小鼠大脑中 sAPPalpha 的含量并减少了 Abeta40 的含量。鉴于 8-(1-癸炔基)-苯内酰胺取得的有希望的动物数据以及我们在苯内酰胺 (BL) SAR 方面的长期经验，我们建议进行一项高度集中的研究，旨在确定可作为治疗 AD 的临床候选药物的最佳苯内酰胺类似物。为了实现这一目标，我们的目标如下： 1. 使用分子建模工具进行化合物设计和新型 BL 的化学合成，旨在优化对 α 分泌酶活性的影响，同时减少任何可能的肿瘤促进活性；这项工作的大部分将集中于改变侧链附件的性质； 2. 进行体外研究以确定新类似物的生物活性。筛选所有化合物作为 PKC 激活剂的活性。测试选定的有效 PKC 激活剂（EC50 至少 50 nM）对 sAPPalpha 和 Abeta 1-40 和 1-42 水平的影响。测试有效增强 sAPPalpha 产生以促进肿瘤生长的化合物； 3. 对于目标 2 中的最佳化合物，在三重转基因小鼠中进行研究，以确定对 Abeta 和 sAPPalpha 水平以及体内斑块形成的影响。