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

基本信息

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
项目类别：
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

项目摘要

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）：大脑的缺血性损伤是导致死亡和发病率的主要原因，通常会导致长期残疾。 NMDA受体（NMDAR）阻滞剂，尤其是针对NR2B-Subunit的阻滞剂是缺血性疾病动物模型的神经保护剂。不幸的是，由于记忆障碍，共济失调，高血压和精神病行为等不可接受的副作用，大多数NMDAR拮抗剂在临床发育中都失败了。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学的酸性pH值下更有效的NMDAR阻滞剂。我们设想开发一种在正常脑pH下实际上无活跃的药物，但一旦pH下降，在缺血性脑组织中迅速阻塞NMDAR，在I期SBIR中，我们确定了概念证明，即小鼠短暂性局灶性局部缺血期间的pH值足够深，足以大大增强我们最佳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以高于治疗水平的神经化合物的剂量，其效力最大。我们已经在亚蛛网膜下腔出血后选择了血管痉挛后的缺血性损伤作为我们的最初临床指示。接下来的下一步是确定临床候选分子及其用于正式临床前开发的备份。这需要沿着非效率（即ADMET）线的我们化合物的铅优化，并确定与临床指示相关的动物模型中一系列化合物的安全边缘。预计这些努力将产生强大的治疗候选者，这些候选者将使用GLP/GMP等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神经化合物进行铅优化研究，确定与缺血相关的临床指示的最佳安全边缘的化合物，并根据从执行AIM 1和2获得的信息选择临床候选者。备份。人类苦难和经济成本因缺血性损伤而产生的人类苦难和经济成本是巨大的。在美国，仅中风的总成本为每年568亿美元（美国心脏病协会，心脏病和中风统计2005年更新）。该项目的目的是开发一种安全有效的药物，以预防和治疗由缺血引起的中枢神经系统损害。