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: 7291537
• 负责人: SCOTT James MYERS
• 金额: $ 63.74万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291537
• 关键词: Adverse effects; American Heart Association; Animal Disease Models; Animal Model; Ataxia; Basic Science; Behavior; Behavioral Symptoms; Biological Assay; Brain; Brain Injuries; Cardiovascular system; Cause of Death; Characteristics; Chemicals; Clinical; Clinical Trials; Depth; Development; Disease; Dose; Drops; Economics; Effectiveness; Exhibits; Glutamate Receptor; Goals; Half-Life; Heart Diseases; Human; Hypertension; Injection of therapeutic agent; Injury; Ischemia; Ischemic Brain Injury; Lead; Lung; Mediating; Medical; Memory impairment; Metabolic; Modeling; Modification; Morbidity - disease rate; Motor Activity; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neuroprotective Agents; Oral; Parkinson Disease; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Plasma; Preparation; Purpose; Receptor Activation; Safety; Series; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Stroke; Structure-Activity Relationship; Subarachnoid Hemorrhage; Therapeutic; Tissues; Toxic effect; Translating; United States; United States Food and Drug Administration; Update; Vasospasm; base; brain tissue; concept; cost; disability; inhibitor/antagonist; man; neuropathology; neuroprotection; novel; painful neuropathy; pre-clinical; preclinical study; prevent; programs; receptor; research clinical testing; social; statistics

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，通常导致长期残疾。NMDA受体（NMDAR）阻断剂，特别是靶向NR 2B亚基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，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理学的酸性pH特征下更有效的NMDAR阻断剂的化合物。我们设想开发一种药物，其在正常脑pH下几乎无活性，但一旦pH下降就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的pH下降足够深，以实质上增强我们最好的NMDAR阻断剂作为神经保护剂的有效性。我们还发现，NMDAR阻断剂的典型不良反应在远高于NeurOp化合物的治疗水平的剂量下不存在，所述NeurOp化合物具有最大的pH值增强效力。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的初始临床适应症。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非功效（即，ADMET）线，以及确定一系列化合物在与临床适应症相关的动物模型中的安全范围。预计这些努力将产生强有力的治疗候选药物，这些候选药物将值得使用支持向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，确定具有缺血相关临床适应症的最佳安全范围的化合物，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。由缺血性损伤引起的人类痛苦和经济成本是巨大的。在美国，每年仅中风的总成本就为568亿美元（美国心脏协会，心脏病和中风统计数据-2005年更新）。本课题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。