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

用于治疗的上下文依赖性 NMADR 神经保护剂的临床前开发

• 批准号: 8122946
• 负责人: George Walter Koszalka
• 金额: $ 29.95万
• 依托单位: NEUROP, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122946
• 关键词: Adverse effects; Adverse event; American; American Heart Association; Aneurysm; Brain; Brain Injuries; Cardiovascular Physiology; Cardiovascular Surgical Procedures; Cause of Death; Cerebral Ischemia; Characteristics; Clinical; Clinical Trials; Clip; Cognitive; Coupling; Data; Development; Dose; Dose-Limiting; Drug Formulations; Drug Industry; Drug effect disorder; Event; Exhibits; Failure; Generations; Goals; Heart Diseases; Intensive Care; Ischemia; Lead; Medical; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroprotective Agents; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiological; Plasma; Population; Pre-Clinical Model; Property; Receptor Inhibition; Relative (related person); Risk; Safety; Site; Stroke; Structure; Subarachnoid Hemorrhage; Sum; Testing; Therapeutic; Time; Tissues; Toxic effect; Traumatic Brain Injury; Update; Vascular blood supply; Work; brain tissue; cerebrovascular; chemical group; cognitive function; cost; disability; drug candidate; early onset; experience; improved; innovation; interstitial; neuroprotection; novel; patient population; pre-clinical; preclinical safety; prevent; prophylactic; receptor; restraint; social; statistics

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.

描述（由申请人提供）：脑缺血是死亡和长期残疾的主要原因，伴随着较高的社会和医疗费用。每年约有795,000名美国人的中风，估计每年$ 73.7B（美国心脏病与中风统计，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，在脑缺血的临床试验中，没有通过该靶标的药物成功，这主要是由于两个问题：i）阻止使药物水平足以达到功效的不良反应； ii）ii）临床限制，这些临床限制在缺血后短时间阻止药物给药。我们正在使用多管齐下的策略来克服这些障碍，以发展上下文依赖性，pH敏感的NR2B亚基选择性NMDA受体拮抗剂，以预防性在亚蛛网膜下腔出血（SAH）中使用。 SAH患者在手术后四到14天经历类似中风的缺血性事件的风险很高，以围绕或夹住动脉瘤。 NR2B选择性拮抗剂与非选择性NMDA拮抗剂的早期几代人本质上的耐受性更好。此外，我们的药物化学和药理学组发现并优化了对NR2B受体抑制选择性的化合物，这些化合物在局灶性局部缺血中比非渗透性组织的半肿瘤区域的间质酸性pH值更有效。更重要的是，在非缺血性组织中，相对缺乏NMDA受体阻滞，生理pH的健康组织可最大程度地减少促进靶向的认知和精神病性不良反应的潜力，而这些不良效果限制了先前的药物。由于我们化合物的上下文依赖性，半月选择性作用，我们预计药物耐受性会有了显着改善，可以在SAH患者动脉瘤手术后的14天内进行缺血之前进行预防性给药。因此，我们的IND候选者将用于神经保护性NMDA受体阻滞，处于继发性缺血的部位，也是最早发作。此处提出的工作旨在通过利用NR2B选择性NMDA受体阻滞的固有功效和耐受性来确定适合预防性使用的新型神经保护剂。 公共卫生相关性：脑缺血描述了大脑血液供应不足的许多情况。脑缺血可能是由中风，脑损伤引起的，或者可能在心血管手术期间发生。这是死亡和残疾的重要原因。没有批准保护脑组织免受缺血诱导损害的药物。我们建议开发一种新型药物，以保护大脑免受脑缺血造成的损害。