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

描述（由申请人提供）：脑缺血是导致死亡和长期残疾的主要原因，伴随的社会和医疗费用很高。美国心脏协会（American Heart Association）估计，每年约有79.5万美国人患中风，造成的损失为737亿美元。心脏病和中风统计，2010年更新)。大量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，还没有药物通过这个靶点在脑缺血的临床试验中取得成功，这主要是由于两个问题：1)不良反应阻碍了药物达到足够的疗效水平；2)临床限制阻碍了在缺血后短时间内给药。我们正在采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、NR2B亚基选择性NMDA受体拮抗剂，用于预防蛛网膜下腔出血（SAH）。SAH患者在动脉瘤缠绕或夹闭手术后4 - 14天内，有发生卒中样缺血事件的风险。与早期的非选择性NMDA拮抗剂相比，NR2B选择性拮抗剂具有更好的耐受性。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半影区间质酸性pH值特征下比非缺血组织更有效。更重要的是，在生理pH值下的非缺血健康组织中，NMDA受体阻滞的相对缺乏最大限度地减少了靶向认知和拟精神不良反应的可能性，这些不良反应限制了先前的候选药物。由于我们的化合物具有环境依赖性、半阴影选择性作用，我们预计药物耐受性会有显著改善，允许SAH患者在动脉瘤手术后14天缺血前预防性给药。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病的神经保护性NMDA受体阻断。本文提出的工作旨在利用ph依赖性受体阻断与nr2b选择性NMDA受体阻断的内在功效和耐受性相结合的优势，鉴定一种适合预防性使用的新型神经保护剂。

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.