pH-Sensitive Glutamate Receptor Inhibitors: Clinical Candidate Selection

描述(申请人提供)：脑缺血损伤是导致死亡和发病的主要原因，通常会导致长期残疾。NMDAR阻滞剂，特别是针对NR2B亚单位的阻断剂，在缺血性疾病动物模型中具有神经保护作用。不幸的是，由于记忆障碍、共济失调、高血压和精神行为等不可接受的副作用，大多数NMDAR拮抗剂在临床开发中都失败了。我们已经确定了一种克服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理的酸性pH特征下更有效的NMDAR阻滞剂。我们设想开发一种药物，这种药物在正常脑pH下几乎没有活性，但一旦pH下降，就会迅速阻断缺血脑组织中的NMDAR，在I阶段SBIR中，我们建立了概念证据，证明在小鼠短暂性局灶性脑缺血期间，pH下降足够深，足以大幅提高我们最好的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并不存在于远高于NeurOp化合物治疗水平的剂量，这些化合物具有最大的pH提升效力。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步临床指征。下一步的关键是确定临床候选分子及其对正式临床前开发的支持。这需要按照非疗效(即ADMET)路线对我们的化合物进行优化，并在与临床适应症相关的动物模型中确定一系列化合物的安全边际。这些努力预计将产生强有力的治疗候选药物，这些候选药物将值得进行正式的临床前研究，使用支持向FDA提交IND所需的GLP/GMP级材料。第二阶段的目标是：对NeurOp化合物进行领先的优化研究，确定与缺血相关的临床适应症具有最佳安全边际的化合物，并根据执行AIMS 1和2所获得的信息选择临床候选及其备份。缺血损伤造成的人类痛苦和经济成本是巨大的。在美国，仅中风每年的总成本就达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脑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.