TREATMENT OF ISHEMIC STROKE BY CASPASE 3 INHIBITION

通过抑制 CASPASE 3 治疗缺血性中风

• 批准号: 6144581
• 负责人: MICHAEL R KOZLOWSKI
• 金额: $ 10万
• 依托单位: TELIK, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2001-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6144581
• 关键词: CD95 molecule; apoptosis; cell line; chemical structure function; cysteine endopeptidases; drug design /synthesis /production; drug discovery /isolation; enzyme inhibitors; protein binding; stroke; stroke therapy

Stroke affects 500,000 people a year, of whom 150,000 will die, making it the leading cause of death, and one of the major causes of neurological disability, in the United States . Of those who survive a stroke, there is significant chance of major disability. It is estimated that more than 26 billion dollars are spent each year on direct medical costs for stroke survivors. The great majority of strokes (>80%) are ischemic in nature. In ischemic stroke, a large portion of the neural damage occurs not as a result of the initial insult, but in the following hours and days. Recent evidence suggests that this delayed neuronal death is an apoptotic process in which caspase 3 plays a critical role. Thus, caspase 3 inhibition may provide a novel treatment modality for ischemic stroke. This program will apply a proprietary drug discovery technology (TRAP) to identify small molecule caspase 3 inhibitors. Based on these inhibitors, a medicinal chemistry effort will produce compounds with sufficient potency and specificity to test, using animal models, the hypothesis that caspase 3 inhibition is effective against transient brain ischemia as well as to serve as starting points for the development of drugs to treat stroke in humans. PROPOSED COMMERCIAL APPLICATIONS: Compounds that diminish neuronal loss due to an ischemic event will be useful therapeutic agents for the management of strokes.

中风每年影响 500,000 人，其中 150,000 人死亡，使其成为美国的首要死因，也是神经功能障碍的主要原因之一。中风幸存者很可能会出现严重残疾。据估计，每年用于中风幸存者的直接医疗费用超过 260 亿美元。绝大多数中风（>80%）本质上是缺血性的。在缺血性中风中，很大一部分神经损伤不是由最初的损伤造成的，而是在接下来的几小时和几天内发生的。最近的证据表明，这种延迟性神经元死亡是一种细胞凋亡过程，其中 caspase 3 发挥着关键作用。因此，Caspase 3 抑制可能为缺血性中风提供新的治疗方式。该计划将应用专有的药物发现技术 (TRAP) 来识别小分子 caspase 3 抑制剂。基于这些抑制剂，药物化学工作将产生具有足够效力和特异性的化合物，以使用动物模型测试 caspase 3 抑制有效对抗短暂性脑缺血的假设，并作为开发药物的起点治疗人类中风。拟议的商业应用：减少由于缺血事件引起的神经元损失的化合物将成为治疗中风的有用治疗剂。