A Novel Family of Neuroprotective Compounds for Stroke

中风是全世界主要的死亡原因，随着寿命的延长和肥胖相关的血管疾病，中风的患病率正在增加。然而，有效的疗法寥寥无几。在过去的几年里，我们已经确定了一种广泛的用于中风的神经保护铅化合物，并合成了一系列衍生品，分为两类。一组具有BDNF样活性，并在细胞培养中活跃于葡萄糖饥饿、氧化应激和营养因子撤除的检测中。在某些检测中，最好的铅的EC50低于10纳摩尔。另一组抑制谷氨酸诱导的兴奋性毒性，但需要通过组合和药物化学来改善，以降低其EC50。这两组化合物在体外缺血的细胞培养模型中都是有效的。我们最初的一条线索增强了啮齿动物的记忆，并在兔脑缺血模型中起到了神经保护作用。这项建议的目标是通过合成化学合成并改善这两类药物的药理性质，并确定其特定的靶点和导致神经保护的分子途径。这些信息不仅将帮助我们改进我们的药物，而且还为确定新的药物开发目标提供了可能性。最后，这些化合物将被单独和组合放入一个严格的兔缺血模型中，以确定它们在临床开发中的潜力。我们认为，在这项工作结束时，我们将识别出一类全新的神经保护化合物，了解它们的功能，并证明它们在中风临床前开发的可行性。

Stroke is a major cause of death throughout the world and its prevalence is increasing with increased longevity and obesity-associated vascular disease. There are, however, very few effective therapeutics. During the last few years we have identified a broadly neuroprotective lead compound for stroke and have synthesized a series of derivatives that fall into two classes. One group has BDNF-like activity and is active in cell culture assays for glucose starvation, oxidative stress, and trophic factor withdrawal. The best lead has an EC50 in some of these assays below 10 nanomolar. The other group inhibits glutamate-induced excitotoxicity, but needs to be improved via combinatorial and medicinal chemistry to lower its EC50. Both groups of compounds are active in cell culture models of in vitro ischemia. One of our initial leads enhances memory in rodents and is neuroprotective in a rabbit ischemia model. It is the goal of this proposal to synthesize and improve the pharmacological properties of both classes of drugs through synthetic chemistry and to identify their specific targets and molecular pathways that lead to neuroprotection. This information will not only help us improve our drugs but also open the possibility of identifying new targets for drug development. Finally, these compounds will be put into a rigorous rabbit ischemia model both individually and in combination to determine their potential for clinical development. We feel that at the end of this work we will have identified a completely new class of neuroprotective compounds, understand how they function, and demonstrated the feasibility for their pre-clinical development for stroke.