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

描述（由申请人提供）：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。每年大约有795，000名美国人遭受中风，估计每年花费737亿美元（美国心脏协会）。心脏病和中风统计，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，迄今为止，通过该靶点起作用的药物在脑缺血的临床试验中尚未成功，这主要是由于两个问题：i）阻止达到足以达到功效的药物水平的不良反应，以及ii）阻止在功效所需的缺血后短时间内给药的临床限制。我们正在使用多管齐下的策略来克服这些障碍，开发一种环境依赖性，pH敏感性，NR 2B亚基选择性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至14天内有发生卒中样缺血事件的巨大风险，以弹簧圈或夹闭动脉瘤。NR 2B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已经发现并优化了对NR 2B受体抑制具有选择性的化合物，这些化合物在局灶性缺血的半影区的间质酸性pH特征下比非缺血组织更有效。更重要的是，在生理pH下非缺血性健康组织中相对缺乏NMDA受体阻断，这使具有有限的先前候选药物的靶向认知和拟精神病不良反应的可能性最小化。由于我们的化合物的环境依赖性、半暗带选择性作用，我们预期药物耐受性显著改善，允许SAH患者动脉瘤手术后14天内在缺血前预防性给药。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作部位的神经保护性NMDA受体阻滞。这里提出的工作旨在确定一种新的神经保护剂，适合于预防性使用，利用耦合的pH依赖性受体阻滞剂的内在疗效和耐受性的NR 2B-选择性NMDA受体阻滞剂。

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.