A Novel Family of Neuroprotective Compounds for Stroke

中风是全世界死亡的主要原因之一，随着寿命的延长和与肥胖相关的血管疾病的增加，其患病率也在增加。然而，很少有有效的治疗方法。在过去的几年里，我们已经确定了一种广泛的中风神经保护先导化合物，并合成了一系列的衍生物，分为两类。一组具有bdnf样活性，在葡萄糖饥饿、氧化应激和营养因子戒断的细胞培养试验中表现活跃。在某些测试中，最好的铅的EC50值低于10纳摩尔。另一组抑制谷氨酸诱导的兴奋性毒性，但需要通过联合和药物化学来提高其EC50。两组化合物在体外缺血细胞培养模型中均有活性。我们最初的一种铅可以增强啮齿动物的记忆，并在兔子缺血模型中起到神经保护作用。本提案的目标是通过合成化学来合成和改善这两类药物的药理学特性，并确定它们的特定靶点和导致神经保护的分子途径。这些信息不仅可以帮助我们改进药物，还可以为药物开发确定新的靶点。最后，这些化合物将单独或联合放入严格的兔缺血模型中，以确定它们的临床开发潜力。我们认为，在这项工作结束时，我们将确定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.