Discovery of a New Class of Neuroproductive Compounds

描述（由申请人提供）：长期目标是开发一类新的小分子化合物，具有神经保护作用，并对未来的药物开发有吸引力。短期目标是发现能够保护机体免受缺氧缺血（HI）引起的脑损伤的化合物，并具有适当的分子特性，可作为未来药物开发的先导化合物。HI诱导的组织损伤是跨越多个疾病领域的主要问题。HI引起的脑损伤，如在中风中发现的，是特别令人关注的，因为幸存者的功能受损以及每年大量死亡。目前，在这一重大疾病领域对安全有效的治疗方法的需求尚未得到满足。患者的临床表现是这样的，治疗窗口在创伤后4到6小时开始，这对候选新药提出了强劲的需求。神经死亡从患者的初始损伤部位向外扩散以及动物模型中发生的病理变化已将人们的注意力集中在程序性细胞死亡上，但对该机制的晚期靶向却令人失望。因此，在细胞承诺死亡之前靶向途径中的早期步骤是关键。诱导死亡的蛋白激酶是早期机制，已被确定为潜在的治疗靶点，并且通过激酶抑制剂穿越血脑屏障的可行性研究为激酶抑制预防HI诱导的脑损伤提供了概念证明。我们建议(1)使用含有结合但无活性化合物的目标激酶结构域的共晶结构作为起点(2)结构辅助合成设计，合成和测试潜在先导化合物的重点文库，以及(3)在体内动物模型中验证最终产品。我们假设，基于结构的分子片段方法，在细胞机制和临床需要的生物学背景下使用，将为这一高风险研究和开发领域产生所需的先导化合物。此次成功完成将有助于验证这种基于结构的药物化学方法的新兴用途，在中枢神经系统发现化学中未满足需求的领域提供对血脑屏障外显率和功效的分子特性的关键见解，并为体内信号转导研究产生广泛有用的试剂。

DESCRIPTION (provided by applicant): The long-term objective is to develop a new class of small molecule compounds that are neuroprotective and attractive for future drug development. The short term goal is the discovery of compounds that will confer protection from hypoxia-ischemia (HI) induced brain injury, and have the appropriate molecular properties to serve as lead compounds in future drug development. HI induced tissue injury is a major problem across multiple disease areas. HI induced brain injury, such as found in stroke, is of special concern because of the compromised function of individuals who survive as well as the significant number of deaths each year. Currently, there is an unmet need for safe and effective therapies in this major disease area. The clinical presentation of patients is such that the therapeutic window starts four to six hours after trauma, placing a robust demand on candidate new drugs. The spreading of neuronal death away from the site of initial injury in patients and the pathological changes that occur in animal models have focused attention on programmed cell death, but targeting of late stages in the mechanism have proven disappointing. Therefore, targeting early steps in the pathway prior to cell commitment to death is key. Death inducing protein kinases are early in the mechanism, have been identified as potential therapeutic targets, and feasibility studies with kinase inhibitors that cross the blood brain barrier have provided a proof of concept for kinase inhibition preventing HI induced brain injury. We propose to (1) use the co-crystal structures of the target kinase domain containing bound but inactive compounds as the starting point for (2) structure assisted synthetic design, synthesis and testing of focused libraries of potential lead compounds, and (3) validation of final products in an in vivo animal model. We hypothesize that the structure based molecular fragment approach, used in the context of biological considerations of cellular mechanism and clinical needs, will yield the required lead compounds for this high-risk area of research and development. The successful completion will help validate the emerging use of this structure based approach to medicinal chemistry, provide insight into molecular properties key for blood brain barrier penetrance and efficacy in an area of unmet need in CNS discovery chemistry, and generate broadly useful reagents for in vivo signal transduction research.