pH-Sensitive Glutamate Receptor Inhibitors: Clinical Candidate Selection

描述（由申请人提供）：脑缺血性损伤是导致死亡和发病的主要原因，并经常导致长期残疾。NMDA受体（NMDAR）阻滞剂，特别是靶向nr2b亚基，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（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，即发现在涉及局灶性缺血的神经病变的酸性pH特征下更有效的NMDA阻滞剂的化合物。我们设想开发一种药物，它在正常脑pH值下几乎无活性，但一旦pH值下降，就会迅速阻断缺血脑组织中的NMDAR。在第一阶段的SBIR中，我们建立了概念证明，即小鼠短暂局灶性缺血期间pH值下降的深度足以大大提高我们最好的NMDAR阻滞剂作为神经保护剂的有效性。我们还发现，NMDAR阻滞剂的典型不良反应在剂量远高于治疗水平的NeurOp化合物中不存在，其效力最大的ph值提升。我们选择蛛网膜下腔出血后血管痉挛引起的缺血性损伤作为我们最初的临床指征。接下来的关键步骤是确定临床候选分子及其正式临床前开发的备份。这需要我们的化合物沿着无疗效（即ADMET）线进行先导优化，同时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边际。这些努力有望产生强大的候选治疗药物，值得使用GLP/GMP级材料进行正式的临床前研究，以支持向FDA提交IND。第二阶段的目标是：对NeurOp化合物进行先导优化研究，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份。缺血性损伤造成的人类痛苦和经济损失是巨大的。在美国，每年仅中风的总费用就高达568亿美元（美国心脏协会，心脏病和中风统计-2005年更新）。本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。

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.