Use of Novel Cox-2 Inhibitors in Neurological Disorders

描述(由申请人提供)：旨在限制和修复氧化应激造成的损害的策略可能会减缓许多与年龄相关的疾病的进展。大量研究表明，环氧合酶-2(COX-2)是由氧化应激诱导的，参与氧化应激，并促进随后的神经元损伤。在这项申请中，我们建议继续我们在第一阶段SBIR拨款下进行的研究，以寻找合适的COX-2抑制剂新化学实体(NCEs)来解决氧化应激诱导的神经细胞损伤。建议的拨款申请的总体目标是推进我们对这些NCEs临床应用的一种新活动的初步发现。在第一阶段授予期间，我们确定了某些Onconova COX-2抑制剂(On 09和On 26系列的类似物)，但不是其他商业上可用的Coxibs，可以防止体外氧化应激诱导的程序性神经细胞死亡。此外，我们还证明，全身应用非选择性COX抑制剂萘普生，部分但有效地防止了谷氨酸激动剂N-甲基-D-天冬氨酸(NMDA)直接注入海马区所引起的损伤。因此，本二期研究计划的目标如下：1)确定一种新的COX-2化合物(On 26040)在体内对抗氧化应激诱导的神经元损伤的治疗潜力。将进行研究，以确定ON 26040是否可以有效地预防a)直接海马注射N-甲基-D-天冬氨酸和/或b)纹状体损伤与全身注射3-硝基专有酸相关的损伤；2)在体外确定ON 26040神经保护作用的分子机制。研究将利用HCA损伤模型来分析COX依赖和/或独立的死亡抑制机制。具体地说，将探索ON 26040调节Akt/PKB和细胞外信号调节激酶信号转导通路的能力；3)开发ON 26040的临床前安全性和药理学概况，以供监管机构提交。研究将包括在大鼠和狗身上进行短期(7天)和长期(28天)重复剂量毒理学研究，以及在体外和体内模型(啮齿动物和犬)中进行完整的药理学评估。具体地说，这一完整的临床前评估包将允许提交用于人体临床研究的研究性新药(ND)申请；以及4)开发用于在人体志愿者身上测试ON 26040安全性的临床第一阶段方案。这将包括根据动物模型选择适当的临床治疗适应症，并为FDA和IRB批准的研究建立剂量、测试和监测指南，该研究将在本文建议的研究完成后进行。

DESCRIPTION (provided by applicant): Strategies aimed at limiting and repairing the damage attributed to oxidative stress may slow the advance of numerous age-related diseases. Numerous studies indicate that the enzyme cyclooxygenase-2 (COX-2) is induced by oxidative stress, contributes to oxidative stress, and promotes subsequent neuronal injury. In this application we propose continuation of our studies carried out under a Phase I SBIR grant to identify suitable COX-2 inhibitor new chemical entities (NCEs) to address oxidative stress-induced damage to the neuronal cells. The overall aim of the proposed grant application is to advance our initial discovery of a novel activity toward a clinical application of these NCEs. During the Phase I grant period, we established that certain Onconova COX-2 inhibitors (analogs of the ON 09 and ON 26 series), but not other commercially available COXibs, prevented oxidative stress-induced programmed neuronal cell death in vitro. Additionally, we demonstrated that systemic administration of naproxen, a non-selective COX inhibitor, partially but potently prevented the injury induced by direct intrahippocampal injection of the glutamate agonist, N-methyl- D-Aspartate (NMDA). Thus, the objectives of this Phase II research plan of study are as follows: 1) to determine the therapeutic potential of a novel COX-2 compound (ON 26040) against oxidative stress-induced neuronal injury in vivo. Studies will be undertaken to identify whether ON 26040 can effectively prevent injury induced by a) direct hippocampal injection of NMDA and/or b) striatal injury associated with systemic injection of 3-nitroproprionic acid; 2) To identify the molecular mechanism mediating the neuroprotective effects of ON 26040 in vitro. Studies will utilize the HCA injury model to analyze COX-dependent and/or -independent mechanisms of death suppression. Specifically, the ability of ON 26040 to modulate the Akt/PKB and extracellular signal-regulated kinase (ERK) signal transduction pathways will be explored; 3) to develop a pre-clinical safety and pharmacology profile of ON 26040 for regulatory submission. Studies will involve short term (7 day) and long term (28 day) repeat dose toxicology studies in rats and dogs and complete pharmacological assessment in both in vitro and in vivo models (rodents and canines). Specifically, this complete pre-clinical evaluation package will permit filing of an Investigational New Drug (ND) application for human clinical studies; and 4) To develop a clinical Phase I protocol for testing the safety of ON 26040 in human volunteers. This will involve selection of appropriate clinical therapeutic indication based on animal models and the establishment of dosing, testing and monitoring guidelines for an FDA and IRB approved study to be conducted following the completion of studies proposed herein.