Discovery of a New Class of Neuroproductive Compounds

发现一类新的神经生产化合物

• 批准号: 6805225
• 负责人: Daniel Martin Watterson
• 金额: $ 24.04万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805225
• 关键词: cerebral ischemia /hypoxia; chemical structure function; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; kinase inhibitor; laboratory rat; neuroprotectants

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.

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，对未来的药物开发有吸引力。短期目标是发现可以保护低氧 - 缺血（HI）诱导脑损伤的化合物，并具有适当的分子特性，可作为未来药物开发的铅化合物。 HI诱导的组织损伤是多种疾病地区的主要问题。 HI诱导的脑损伤（例如中风中发现）特别关注，因为每年生存以及大量死亡的人的功能受损。当前，在这个主要疾病领域需要对安全有效的疗法满足。患者的临床表现使得治疗窗口在创伤后四到六个小时开始，对候选新药的需求强劲。神经元死亡从患者的初始损伤部位以及动物模型中发生的病理变化的扩散已将注意力集中在程序性细胞死亡上，但事实证明，该机制中的晚期靶向已令人失望。因此，在细胞承诺死亡之前，针对途径的早期步骤是关键。死亡诱导蛋白激酶在该机制的早期已经被确定为潜在的治疗靶标，并且对跨血脑屏障的激酶抑制剂的可行性研究为防止HI诱导的脑损伤的激酶抑制提供了概念证明。我们建议（1）使用含有绑定但无活性化合物的靶激酶结构域的共晶结构，作为（2）结构辅助合成设计，合成和测试潜在铅化合物的集合和测试的起点，以及（3）在体内动物模型中对最终产品的验证。我们假设在细胞机制和临床需求的生物学考虑方面使用的基于结构的分子碎片方法将为这一高风险的研究和开发领域提供所需的铅化合物。成功的完成将有助于验证这种基于结构的药物化学方法的新兴使用，从而深入了解分子特性在CNS发现化学中未满足的领域中血液脑屏障的渗透和功效的关键，并为体内信号转导研究生成广泛有用的试剂。