Development of Anti-necrosis Drug for Acute Brain Injury

急性脑损伤抗坏死药物的研制

• 批准号: 7100711
• 负责人: JUNYING YUAN
• 金额: $ 126.13万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100711
• 关键词: brain injury; cell death; ischemia; lead; model; necrosis

DESCRIPTION (provided by applicant): The objective of this proposal is to develop necrostatins that inhibit necroptosis, a type of programmed necrosis, as a novel therapy for acute brain injury. Apoptosis plays a critical role in physiological neuronal cell death and also contributes to pathological neuronal cell death. However, evidence is accumulating that cells possess an alternative mechanism of cell death which when activated induces cell death with features of necrosis which we termed "necroptosis". Nine structurally distinct classes of small molecule inhibitors of necroptosis, termed necrostatins, have been identified from screening approximately 100,000 compounds. Preliminary "proof-of-concept" work has demonstrated in vivo efficacy of a necrostatin in reducing ischemic brain injury with a prolonged time window. The plan is to expand this effort by screening an additional 100,000 compounds (Specific Aim 1). The pool of necrostatins will be analyzed in primary neurons for protection against oxygen and glucose deprivation and in mouse model of middle cerebral artery occlusion in vivo by icv delivery to select at least two lead compounds for further optimization (Specific Aim 2). Medicinal chemistry will be carried out to improve the efficacy and bio-availability of the lead compounds and to reduce toxicity (Specific Aim 3). The efficacy of lead compounds in inhibiting acute brain injury will be analyzed systematically using rodent models of ischemic brain injury and in a large animal model of ischemic brain injury (Specific Aim 4). The lead compound series will be analyzed for their pharmacokinetic, ADME and toxicology profiles. Finally, a pre-clinical candidate with efficacy in cerebral ischemia in a large animal and clean safety pharmacology will be selected for clinical development. Drug product for a Phase 1 study will be manufactured under GMP conditions with GLP analytics, and further toxicology (GLP) and safety pharmacology studies will be conducted (Specific Aim 5). This project will culminate with the filing of an IND application with the FDA in order to enter a Phase I human clinical trial.

描述（由申请人提供）： 该提案的目的是开发抑制坏死性凋亡（一种程序性坏死）的坏死抑素，作为急性脑损伤的新型疗法。细胞凋亡在生理性神经元细胞死亡中起着关键作用，也导致病理性神经元细胞死亡。然而，越来越多的证据表明，细胞拥有另一种细胞死亡机制，当该机制被激活时，会诱导具有坏死特征的细胞死亡，我们称之为“坏死性凋亡”。通过筛选大约 100,000 种化合物，已鉴定出九种结构不同的坏死性凋亡小分子抑制剂，称为坏死抑素。初步的“概念验证”工作已经证明了坏死他汀在延长时间窗内减少缺血性脑损伤的体内功效。该计划旨在通过筛选另外 100,000 种化合物来扩大这项工作（具体目标 1）。将在原代神经元中分析坏死他汀库，以防止缺氧和葡萄糖剥夺，并在通过静脉注射体内大脑中动脉闭塞的小鼠模型中进行分析，以选择至少两种先导化合物进行进一步优化（具体目标 2）。将进行药物化学以提高先导化合物的功效和生物利用度并降低毒性（具体目标 3）。将使用缺血性脑损伤的啮齿动物模型和缺血性脑损伤的大型动物模型系统地分析先导化合物抑制急性脑损伤的功效（具体目标4）。将分析先导化合物系列的药代动力学、ADME 和毒理学特征。最后，将选择对大型动物脑缺血有效且药理学清洁的临床前候选药物进行临床开发。第一阶段研究的药品将在 GMP 条件下通过 GLP 分析进行生产，并将进行进一步的毒理学 (GLP) 和安全药理学研究（具体目标 5）。该项目最终将向 FDA 提交 IND 申请，以进入 I 期人体临床试验。