Pre-clinical Development of a Context-Dependent NMADR Neuroprotectant for Treatme

描述(申请人提供)：脑缺血是死亡和长期残疾的主要原因，伴随着高昂的社会和医疗成本。每年约有795,000名美国人中风，估计每年的成本为737亿美元(美国心脏协会)。心脏病和中风统计数据，2010年更新)。大量的临床前数据支持使用NMDA受体拮抗剂来减少脑缺血引起的脑损伤。然而，到目前为止，通过这一靶点作用的药物还没有在脑缺血的临床试验中成功，这主要是由于两个问题：i)不良反应阻碍了达到足够疗效的药物水平，ii)临床限制阻止了在缺血后短时间内给药以达到疗效所需。我们正在使用多管齐下的策略来克服这些障碍，开发一种上下文依赖的、pH敏感的、NR2B亚单位选择性的NMDA受体拮抗剂，用于预防蛛网膜下腔出血(SAH)。SAH患者在手术后4到14天有很大的风险经历类似中风的缺血事件，以圈闭或夹闭他们的动脉瘤。NR2B选择性拮抗剂本质上比早期几代非选择性NMDA拮抗剂耐受性更好。此外，我们的药物化学和药理学小组发现并优化了选择性抑制NR2B受体的化合物，这些化合物在局灶性缺血时半暗带区的间质酸性pH特征方面比非缺血组织更有效。更重要的是，在生理pH下，非缺血的健康组织中相对缺乏NMDA受体阻断，最大限度地减少了靶向认知和拟精神分裂症不良反应的可能性，这些不良反应限制了先前的候选药物。由于我们化合物的上下文依赖、半暗带选择性作用，我们预计SAH患者的药物耐受性将显著改善，允许在动脉瘤手术后14天内，在缺血之前预防性给药。因此，我们的IND候选药物将可用于继发性缺血部位和最早发病的神经保护性NMDA受体阻滞剂。本研究旨在利用pH依赖受体阻滞剂与NR2B选择性NMDA受体阻滞剂的内在有效性和耐受性相结合的优势，寻找一种适合于预防性使用的新型神经保护剂。 公共卫生相关性：脑缺血描述了大脑供血不足的许多情况。脑缺血可能由中风、创伤性脑损伤引起，也可能发生在心血管手术期间。它是导致死亡和残疾的重要原因。目前还没有批准的药物可以保护脑组织免受缺血损伤。我们建议开发一种新的药物来保护大脑免受脑缺血造成的损害。

DESCRIPTION (provided by applicant): Cerebral ischemia is a major cause of death and long-term disability, with high accompanying social and medical costs. Approximately 795,000 Americans suffer a stroke each year at an estimated annual cost of $73.7B (American Heart Association. Heart Disease and Stroke Statistics, 2010 Update). Substantial preclinical data support the use of NMDA receptor antagonists to reduce brain damage caused by cerebral ischemia. However, to date no drug acting through this target has been successful in clinical trials of cerebral ischemia, largely due to two issues: i) adverse effects that prevented attaining drug levels adequate for efficacy, and ii) clinical restraints that prevented drug administration within the short time after ischemia required for efficacy. We are using a multi-pronged strategy to overcome these obstacles in the development of a context-dependent, pH-sensitive, NR2B subunit selective NMDA receptor antagonist for prophylactic use in subarachnoid hemorrhage (SAH). SAH patients are at substantial risk of experiencing a stroke-like ischemic event four to 14 days after their surgery to coil or clip their aneurysm. NR2B selective antagonists are intrinsically better tolerated than early generations of non-selective NMDA antagonists. Furthermore, our medicinal chemistry and pharmacology group has discovered and optimized compounds selective for NR2B receptor inhibition that are more potent at the interstitial acidic pH characteristic of the penumbral region in focal ischemia than non-ischemic tissue. More importantly, the relative lack of NMDA receptor block in non- ischemic, healthy tissues at physiological pH minimizes the potential for on-target cognitive and psychotomimetic adverse effects that have limited prior drug candidates. Because of the context-dependent, penumbral-selective actions of our compounds, we anticipate a dramatic improvement in drug tolerability, allowing for prophylactic administration prior to ischemia during the 14 days after aneurysm surgery in SAH patients. Thus, our IND candidate will be available for neuroprotective NMDA receptor block at the site of, and earliest onset of, secondary ischemia. The work proposed here is aimed at identifying a novel neuroprotective agent suitable for prophylactic use by taking advantage of coupling pH-dependent receptor block with the intrinsic efficacy and tolerability of NR2B-selective NMDA receptor blockade. PUBLIC HEALTH RELEVANCE: Cerebral ischemia describes many conditions in which there is inadequate blood supply to the brain. Cerebral ischemia may be caused by stroke, traumatic brain injury or may happen during cardiovascular surgery. It is a significant cause of death and disability. There are no drugs approved that protect brain tissue from ischemia- induced damage. We propose to develop a novel drug to protect the brain from damage caused by cerebral ischemia.