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 （COX-2）是由氧化应激诱导的，有助于氧化应激，并促进随后的神经元损伤。在此申请中，我们建议继续我们在I期SBIR资助下进行的研究，以确定合适的COX-2抑制剂新化学实体（NCEs），以解决氧化应激诱导的神经元细胞损伤。本次拨款申请的总体目标是推动我们对这些nce的临床应用的新活动的初步发现。在I期批准期间，我们确定了某些Onconova COX-2抑制剂（ON 09和ON 26系列的类似物），但不是其他市售的coxib，可以在体外预防氧化应激诱导的程序性神经元细胞死亡。此外，我们证明了全身给予萘普生（一种非选择性COX抑制剂），部分但有效地预防了直接在海马内注射谷氨酸激动剂n-甲基- d -天冬氨酸（NMDA）引起的损伤。因此，本II期研究计划的目的如下：1)确定一种新型COX-2化合物（ON 26040）在体内对氧化应激诱导的神经元损伤的治疗潜力。研究将确定ON 26040是否能有效预防a)直接海马注射NMDA和/或b)全身注射3-硝基本体酸引起的纹状体损伤；2)探讨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cox依赖和/或独立的死亡抑制机制。具体而言，将探讨ON 26040调节Akt/PKB和细胞外信号调节激酶（ERK）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资料，以提交监管部门。研究将包括短期（7天）和长期（28天）大鼠和狗的重复剂量毒理学研究，并在体外和体内模型（啮齿动物和犬类）中完成药理学评估。具体来说，这个完整的临床前评估包将允许提交用于人体临床研究的正在研究的新药（ND）申请；4)制定一项临床I期方案，以测试ON 26040在人类志愿者中的安全性。这将涉及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，该研究将在本文提出的研究完成后进行。

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.