pH-Sensitive Glutamate Receptor Inhibitors: Clinical Candidate Selection

pH 敏感谷氨酸受体抑制剂：临床候选药物选择

• 批准号: 7110898
• 负责人: SCOTT James MYERS
• 金额: $ 76.62万
• 依托单位: NEUROP, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110898
• 关键词: NMDA receptors; ataxia; behavior; brain; brain injury; death; glutamate receptor; heart; hypertension; injury; ischemia; lead; memory; model; neuropathology; neuroprotectants; stroke; subarachnoid hemorrhage; tissues; vasospasm

DESCRIPTION (provided by applicant): Ischemic injury of the brain is a major cause of death and morbidity, and often causes long term disability. NMDA receptor (NMDAR) blockers, particularly targeting the NR2B-subunit are neuroprotective in ischemic disease animal models. Unfortunately, most NMDAR antagonists have failed in clinical development as a result of unacceptable side effects such as memory impairment, ataxia, hypertension and psychotic behavior. We have identified a potential strategy for overcoming NMDA receptor-mediated toxicities, namely to discover compounds that are more effective NMDAR blockers at the acidic pH characteristic of neuropathologies involving focal ischemia. We envision developing a drug that is virtually inactive at normal brain pH but rapidly blocks NMDAR in ischemic brain tissue as soon as the pH drops, in the phase I SBIR we established proof of concept that the pH drop during transient focal ischemia in mice is deep enough to substantially enhance the effectiveness of our best NMDAR blockers as neuroprotectants. We also found that the typical adverse effects of NMDAR blockers are not present at doses well above therapeutic levels for NeurOp compounds with the largest pH-boost in potency. We have selected ischemic injury following vasospasm after subarachnoid hemorrhage as our initial clinical indication. The key next steps are to identify a clinical candidate molecule and its backup for formal preclinical development. This requires lead optimization of our compounds along non-efficacy (i.e., ADMET) lines, together with determination of the safety margin for a series of compounds in animal models related to the clinical indication. These efforts are expected to yield strong therapeutic candidates which will merit formal preclinical studies using GLP/GMP grade materials required to support the submission of an IND to the FDA. The Phase II goals are to; carry out lead optimization studies on NeurOp compounds, identify compounds with the best safety margin for ischemia-related clinical indications and select a clinical candidate and its backup based upon information obtained from performing aims 1 and 2. The human suffering and economic costs resulting from ischemic injury is enormous. The total cost of stroke alone is $56.8 billion per year in the United States (American Heart Association, Heart Disease and Stroke Statistics-2005 Update). The goal of this project is to develop a safe and effective drug to prevent and treat CNS damage caused by ischemia.

描述（由申请人提供）：脑缺血性损伤是死亡和发病的主要原因，并且常常导致长期残疾。 NMDA 受体 (NMDAR) 阻滞剂，特别是针对 NR2B 亚基的阻滞剂，在缺血性疾病动物模型中具有神经保护作用。不幸的是，大多数 NMDAR 拮抗剂由于不可接受的副作用（例如记忆障碍、共济失调、高血压和精神病行为）而在临床开发中失败。我们已经确定了克服 NMDA 受体介导的毒性的潜在策略，即发现在涉及局部缺血的神经病理学的酸性 pH 特征下更有效的 NMDAR 阻滞剂化合物。我们设想开发一种药物，该药物在正常大脑 pH 值下几乎没有活性，但一旦 pH 值下降，就会迅速阻断缺血脑组织中的 NMDAR，在 I 期 SBIR 中，我们建立了概念证明，即小鼠短暂局灶性缺血期间 pH 值下降幅度很大足以大幅增强我们最好的 NMDAR 阻滞剂作为神经保护剂的有效性。我们还发现，当剂量远高于具有最大 pH 提升效力的 NeurOp 化合物的治疗水平时，NMDAR 阻滞剂的典型副作用并不存在。我们选择蛛网膜下腔出血后血管痉挛后的缺血性损伤作为我们的初始临床指征。接下来的关键步骤是确定临床候选分子及其用于正式临床前开发的支持。这需要沿着无功效（即 ADMET）路线对我们的化合物进行先导优化，并确定与临床适应症相关的动物模型中一系列化合物的安全裕度。这些努力预计将产生强大的治疗候选药物，这些候选药物值得使用支持向 FDA 提交 IND 所需的 GLP/GMP 级材料进行正式的临床前研究。第二阶段的目标是：对 NeurOp 化合物进行先导化合物优化研究，确定对缺血相关临床适应症具有最佳安全裕度的化合物，并根据执行目标 1 和 2 获得的信息选择临床候选药物及其备用药物。缺血造成的人类痛苦和经济成本伤害是巨大的。在美国，仅中风的总费用每年就达 568 亿美元（美国心脏协会，心脏病和中风统计 - 2005 年更新）。该项目的目标是开发一种安全有效的药物来预防和治疗缺血引起的中枢神经系统损伤。