PKC Modulators for the Treatment of Alzheimer's disease

描述（由申请人提供）：越来越多的人认为阿尔茨海默病（AD）病理生理学中的关键事件是淀粉样蛋白β肽（Abeta）的过量产生。如果这个公式是正确的，那么有三种主要的策略来中断病理级联：抑制-分泌酶，抑制-分泌酶，或增加-分泌酶。直观地说，如果β是罪魁祸首，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的β所必需的，而α分泌酶在β结构域内分裂，阻止其完整释放。制药行业在开发-和-分泌酶抑制剂方面投入了大量资金，尽管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 -分泌酶的活性。我们增强α -分泌酶活性的方法包括调节蛋白激酶C (PKC)，在许多实验室中，PKC最终与α -分泌酶的调节有关。在这方面，我们最近发现结构新颖的PKC激活剂8-(1-decynyl)-苯内酰胺能够逆转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，该苯内酰胺显著增加了APP[V7171]转基因小鼠大脑中sAPPalpha的数量，降低了Abeta40的数量。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）的SAR方面的长期经验，我们建议进行一项高度集中的研究，旨在确定最佳的苯内酰胺类似物，可以作为治疗AD的临床候选药物。为实现这一目标，我们的目标如下：

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.