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引起的损伤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（考克斯-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。在本申请中，我们建议继续我们在I期SBIR资助下进行的研究，以鉴定合适的考克斯-2抑制剂新化学实体（NCE），以解决氧化应激诱导的神经元细胞损伤。拟议拨款申请的总体目标是推进我们对这些NCE临床应用的新活性的初步发现。在I期授权期间，我们确定了某些Onconova考克斯-2抑制剂（ON 09和ON 26系列的类似物），而不是其他市售的COXib，在体外预防氧化应激诱导的程序性神经元细胞死亡。此外，我们证明，全身给药的napolipen，非选择性考克斯抑制剂，部分但有效地防止直接海马内注射谷氨酸激动剂，N-甲基-D-天冬氨酸（NMDA）诱导的损伤。因此，该II期研究计划的目的如下：1）确定新型考克斯-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由a）直接海马注射NMDA和/或B）与全身注射3-硝基丙酸相关的纹状体损伤诱导的损伤; 2）确定介导ON 26040体外神经保护作用的分子机制。研究将利用HCA损伤模型来分析死亡抑制的COX依赖性和/或非依赖性机制。具体而言，将探索ON 26040调节Akt/PKB和细胞外信号调节激酶（ERK）信号转导途径的能力; 3）开发ON 26040的临床前安全性和药理学特征，以供监管提交。研究将涉及大鼠和犬的短期（7天）和长期（28天）重复给药毒理学研究，以及体外和体内模型（啮齿动物和犬）的完整药理学评估。具体而言，该完整的临床前评价包将允许提交用于人类临床研究的研究性新药（ND）申请;以及4）开发用于测试ON 26040在人类志愿者中的安全性的临床I期方案。这将涉及基于动物模型选择适当的临床治疗适应症，以及为完成本文拟定研究后将进行的FDA和IRB批准的研究制定给药、检测和监测指南。

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.