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: 6584069
• 负责人: STANLEY C BELL
• 金额: $ 10万
• 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 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584069
• 关键词: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; biotherapeutic agent; cerebral ischemia /hypoxia; drug design /synthesis /production; drug discovery /isolation; enzyme inhibitors; glutamate receptor; heterocyclic compounds; laboratory mouse; nervous system disorder chemotherapy; neuropharmacology; neuroprotectants; nonsteroidal antiinflammatory agent; prostaglandin endoperoxide synthase; stroke; tissue /cell culture

DESCRIPTION (provided by applicant): Up-regulation of COX-2 has also been reported to occur in human brains following a lethal cerebral ischemic insult and selective inhibition of COX-2 has been demonstrated to be neuroprotective in animal models. In addition, there has been a voluminous literature that suggests that cyclooxygenase-2 (COX-2) may contribute to neuronal injury in various neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's and Alzheimer's disease. Indeed, numerous studies on the long-term use of NSAID's have demonstrated the improvement or a decrease in the potential of Alzheimer's disease (AD). The decrease in undesirable GI side effects of selective COX-2 has stimulated long-term clinical evaluation studies of current marketed COX-2 inhibitor for AD. We have developed a novel chemotype (Onconova compounds ON 09** Series) with potent and selective COX-2 inhibitory activity. In collaboration with Dr. Sandra Hewett at the University Connecticut Health Center, these compounds are now being applied for various indications including prevention of cancer, inflammation and CNS injury. The specific aims are as follows: Short term; 6 months - Employing the mini library of COX-2 inhibitors created around the new chemotype identified by Onconova, we will evaluate whether inhibition of COX-2 by these drugs in Dr. Hewett's CNS model will be neuroprotective. Specifically, studies will be undertaken to determine the therapeutic potential of these novel COX-2 compounds against NMDA-induced neuronal injury (excitotoxicity) in mixed cortical cell cultures as excitotoxicity has been implicated in the pathogenesis of brain injury triggered by hypoxic-ischemia insults as well as AD. Based on these results, we will employ Structure Activity Relationship (SAR) to prepare additional novel COX-2 compounds for evaluation. We will establish a SAR pattern of activity with our novel series of compounds. Intermediate term - Effective demonstration of neuroprotection in the in vitro model will aid in the identification of interesting and active compounds for in vivo animal studies of neuronal injury associated with over-activation of glutamate receptors, including AD and stroke. Following the identification of a lead compound, production of large quantities of the compound for these studies will be undertaken. Long term - A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations will be carried out internally or with a commercial partner, based on the needs of the company.

描述（由申请人提供）：据报道，COX-2的上调在人的大脑中发生在致命的脑缺血性损伤后，并且已经证明对COX-2的选择性抑制在动物模型中是神经保护性的。此外，还有大量的文献表明环氧合酶-2（COX-2）可能在包括肌萎缩性侧面硬化症，帕金森氏症和阿尔茨海默氏病在内的各种神经退行性疾病中有助于神经元损伤。确实，关于长期使用NSAID的许多研究表明，阿尔茨海默氏病（AD）的潜力有所改善或减少。选择性COX-2的不良GI副作用的减少刺激了当前市场COX-2抑制剂的长期临床评估研究。我们已经开发了一种具有有效和选择性COX-2抑制活性的新型化学型（ONCONOVA化合物）。与大学康涅狄格大学健康中心的桑德拉·休伊特（Sandra Hewett）博士合作，这些化合物现在正在用于各种适应症，包括预防癌症，炎症和中枢神经系统损伤。具体目的如下：短期； 6个月 - 采用围绕OnConova确定的新化学型创建的COX-2抑制剂的迷你库，我们将评估Hewett博士在Hewett博士的CNS模型中对COX-2的抑制作用。具体而言，将进行研究，以确定这些新型COX-2化合物针对NMDA诱导的混合皮质细胞培养物中NMDA诱导的神经元损伤（兴奋性毒性）的治疗潜力，因为兴奋性毒性已与低氧性红血病的疾病触发的脑损伤引起的兴奋性毒性有关。基于这些结果，我们将采用结构活动关系（SAR）来制备其他新型的COX-2化合物进行评估。我们将通过新颖的化合物建立SAR活动模式。中等学期 - 在体外模型中神经保护的有效证明将有助于鉴定有趣且活跃的化合物，用于体内动物研究与谷氨酸受体过度激活相关的神经元损伤，包括AD和中风。鉴定铅化合物后，将进行这些研究的大量化合物。长期 - 成功完成第1阶段的候选人将进一步发展。后来的第2阶段和第3阶段评估的研究将根据公司的需求进行内部或商业合作伙伴进行。