Development of Anti-necrosis Drug for Acute Brain Injury

描述（由申请人提供）： 本提案的目的是开发抑制坏死性凋亡（一种程序性坏死）的坏死抑制素，作为急性脑损伤的新疗法。细胞凋亡在生理性神经元细胞死亡中起关键作用，并且也有助于病理性神经元细胞死亡。然而，越来越多的证据表明，细胞具有另一种细胞死亡机制，当激活时，该机制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，已确定了九种结构不同的坏死性凋亡小分子抑制剂，称为坏死抑制素。初步的“概念验证”工作已经证明了坏死抑制素在延长的时间窗内减少缺血性脑损伤的体内功效。该计划将通过筛选另外100，000种化合物来扩大这一努力（具体目标1）。将在原代神经元中分析necrostatin的库以保护免受氧和葡萄糖剥夺，并在通过icv递送的体内大脑中动脉闭塞的小鼠模型中分析necrostatin的库，以选择至少两种先导化合物用于进一步优化（具体目标2）。将开展药物化学研究，以提高先导化合物的有效性和生物利用度，并降低毒性（具体目标3）。将使用缺血性脑损伤啮齿动物模型和缺血性脑损伤大型动物模型系统分析先导化合物抑制急性脑损伤的疗效（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，将选择在大型动物脑缺血中具有疗效和清洁安全药理学的临床前候选药物进行临床开发。I期研究的制剂将在GMP条件下进行GLP分析，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。

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.