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: 8527861
• 负责人: George Walter Koszalka
• 金额: $ 99.47万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527861
• 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.

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费用。每年大约有 795,000 名美国人遭受中风，估计每年花费 73.7B 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，通过该靶点发挥作用的药物尚未在脑缺血的临床试验中取得成功，这主要是由于两个问题：i）不良反应阻碍了达到足以发挥功效的药物水平，以及ii）临床限制阻碍了在发挥功效所需的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，开发一种背景依赖性、pH 敏感、NR2B 亚基选择性 NMDA 受体拮抗剂，用于预防性蛛网膜下腔出血 (SAH)。 SAH 患者在动脉瘤旋绕或夹闭手术后 4 至 14 天面临发生中风样缺血事件的巨大风险。 NR2B 选择性拮抗剂本质上比早期非选择性 NMDA 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还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暗区的间质酸性 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，最大限度地减少了靶向认知和拟精神病副作用的可能性，而这些副作用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、半影选择性作用，我们预计药物耐受性将显着改善，从而可以在 SAH 患者动脉瘤手术后 14 天内在缺血前进行预防性给药。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的神经保护性 NMDA 受体阻断。本文提出的工作旨在通过利用 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，确定一种适合预防性使用的新型神经保护剂。