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，这些化合物具有神经保护作用，对未来的药物开发具有吸引力。短期目标是发现将赋予对缺氧-缺血（HI）诱导的脑损伤的保护的化合物，并且具有适当的分子性质以在未来药物开发中充当先导化合物。HI诱导的组织损伤是多个疾病领域的主要问题。HI诱导的脑损伤，例如在中风中发现的脑损伤，由于存活个体的功能受损以及每年大量的死亡而受到特别关注。目前，在这一主要疾病领域，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至6小时开始，对候选新药提出了强劲的需求。神经元死亡从患者初始损伤部位的扩散以及动物模型中发生的病理变化使人们关注程序性细胞死亡，但该机制中的晚期阶段的靶向已被证明令人失望。因此，靶向细胞死亡之前的途径中的早期步骤是关键。诱导死亡的蛋白激酶处于机制的早期，已被确定为潜在的治疗靶标，并且使用穿过血脑屏障的激酶抑制剂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靶激酶结构域的共晶体结构作为起点，用于（2）潜在先导化合物的聚焦文库的结构辅助合成设计、合成和测试，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的方法，用于细胞机制和临床需求的生物学考虑的背景下，将产生所需的先导化合物的研究和开发的高风险领域。成功完成将有助于验证这种基于结构的方法在药物化学中的新兴用途，提供对血脑屏障渗透率和CNS发现化学领域未满足需求的有效性的关键分子特性的深入了解，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.