Use of Novel Cox-2 Inhibitors in Neurological Disorders

描述(申请人提供)：据报道，COX-2在致命性脑缺血损伤后在人脑中表达上调，选择性抑制COX-2在动物模型中被证明具有神经保护作用。此外，已有大量文献表明，环氧合酶-2(COX-2)可能在肌萎缩侧索硬化症、帕金森病和阿尔茨海默病等多种神经退行性疾病的神经元损伤中起作用。事实上，许多关于长期使用非类固醇抗炎药的研究已经证明，阿尔茨海默病(AD)的可能性有所改善或降低。选择性COX-2不良胃肠道副作用的减少刺激了目前上市的治疗AD的COX-2抑制剂的长期临床评估研究。我们开发了一种新的化学型(09**系列上的Onconova化合物)，具有有效和选择性的COX-2抑制活性。与康涅狄格大学健康中心的桑德拉·休伊特博士合作，这些化合物现在正被应用于各种适应症，包括预防癌症、炎症和中枢神经系统损伤。具体目标如下：短期；6个月-利用围绕Onconova确定的新化学类型创建的COX-2抑制剂迷你库，我们将评估在休伊特博士的CNS模型中，这些药物对COX-2的抑制是否具有神经保护作用。具体地说，将进行研究，以确定这些新的COX-2化合物在混合皮质细胞培养中对抗NMDA诱导的神经元损伤(兴奋毒性)的治疗潜力，因为兴奋毒性与缺氧缺血损伤和AD引发的脑损伤的发病机制有关。基于这些结果，我们将利用结构活性关系(SAR)来制备更多的新的COX-2化合物用于评估。我们将用我们的新系列化合物建立一种SAR活性模式。体外模型中神经保护的中期有效演示将有助于鉴定有趣的活性化合物，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。在确定了一种铅化合物之后，将为这些研究大量生产这种化合物。长期-成功完成第一阶段的候选人将得到进一步开发。第二阶段和第三阶段评估的后续研究将根据公司的需要在内部或与商业合作伙伴一起进行。

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.