Use of Novel Cox-2 Inhibitors in Neurological Disorders

新型 Cox-2 抑制剂在神经系统疾病中的应用

• 批准号: 6994457
• 负责人: STANLEY C BELL
• 金额: $ 27.42万
• 依托单位: ONCONOVA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-03 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994457
• 关键词: cerebral ischemia /hypoxia; cyclooxygenase inhibitors; dogs; drug design /synthesis /production; embryo /fetus cell /tissue; laboratory mouse; laboratory rat; microinjections; mitogen activated protein kinase; nervous system disorder chemotherapy; neural degeneration; neuropharmacology; neuroprotectants; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; oxidative stress; polymerase chain reaction; western blottings

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.

描述（由申请人提供）：旨在限制和修复归因于氧化应激的损害的策略可能会减慢许多与年龄有关的疾病的发展。大量研究表明，酶环氧酶-2（COX-2）是由氧化应激诱导的，有助于氧化应激，并促进了随后的神经元损伤。在此应用中，我们提出了在I期SBIR拨款下进行的研究，以识别合适的COX-2抑制剂新化学实体（NCE），以解决氧化应激引起的对神经元细胞的损害。拟议的赠款应用程序的总体目的是提高我们最初发现新的活动朝着这些NCE的临床应用的发现。在I阶段的批准期间，我们确定某些OnConova Cox-2抑制剂（ON 09和26系列的类似物），但没有其他市售的Coxibs，可以阻止氧化应激诱导的编程神经元细胞的体外。此外，我们证明了一种非选择性COX抑制剂的萘普生的全身给药，部分但有效地阻止了直接汉皮克接管谷氨酸激动剂N-甲基 - D-大赛（NMDA）引起的损伤。因此，该II期研究计划的目标如下：1）确定新型COX-2化合物（26040）对体内神经元损伤的治疗潜力。将进行研究以确定在26040上是否可以有效预防NMDA的直接海马注射和/或b）与全身注射3-硝基孕酸有关的纹状体损伤； 2）确定介导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依赖性和/或独立的死亡抑制机制。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26040的临床前安全性和药理学概况，以进行调节。研究将涉及大鼠和狗的短期（7天）和长期（28天）重复剂量毒理学研究，并在体外和体内模型（啮齿动物和犬科）中进行完整的药理评估。具体而言，此完整的临床前评估软件包将允许对人类临床研究提出研究新药（ND）申请； 4）制定了I期临床I阶段方案，以测试人类志愿者的26040的安全性。这将涉及根据动物模型选择适当的临床治疗指示，并在本文启用的研究完成后，建立对FDA和IRB认可的研究的剂量，测试和监测指南。