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A Novel Neuroprotectant to Reduce Ischemic Injury

一种减少缺血性损伤的新型神经保护剂

基本信息

批准号：
10576568
负责人：
KLAUS VAN LEYEN
金额：
$ 40.84万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576568
关键词：
12-HETE Adhesives Alteplase Arachidonate 15-Lipoxygenase Arachidonic Acids Binding Biological Assay Blood Bolus Infusion Brain Brain Injuries Brain Ischemia Cause of Death Cerebrovascular system Characteristics Clinical Clinical Research Correlation Studies Data Dose Drug Kinetics Edema Effectiveness Enzymes Excision FDA approved Formulation Future Goals Hemorrhage High Pressure Liquid Chromatography Human Hydroxyeicosatetraenoic Acids In Vitro Infarction Infusion procedures Intravenous Intravenous infusion procedures Ischemic Stroke Lead Lipoxygenase Measures Modeling Morbidity - disease rate Neurons Neuroprotective Agents Outcome Outcome Study Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Plasma Public Health Rattus Recombinants Reperfusion Therapy Rodent Route Sampling Site Standardization Stroke Testing Therapeutic Agents Time United States Walking behavior test brain endothelial cell dosage effective therapy efficacy testing experimental study in vivo inhibitor intraperitoneal intravenous administration ischemic injury mortality mouse model multimodality neuron loss novel novel therapeutics oxidation pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pharmacologic response scaffold side effect small molecule inhibitor specific biomarkers stroke model stroke patient stroke therapy therapeutically effective thromboembolic stroke thrombolysis

项目摘要

The goal is to develop novel therapeutics effective in stroke. This will be achieved by providing evidence for in vivo activity of our lead compound in a rat stroke model as well as supportive pharmacokinetic and pharmacodynamic (PK/PD) assay data. We have identified potent and highly selective inhibitors of the human 12/15 lipoxygenase enzyme, which contributes to brain injury after a stroke by damaging neurons and endothelial cells of the brain. We now want to test our lead compound in a rat model of ischemic stroke, to determine the optimal dosage and time of administration. The effectiveness of the inhibitor will be determined by measuring infarct sizes, as well as the enzyme products formed by 12/15 lipoxygenase in the presence or absence of its inhibitor. These results will then be correlated to the brain exposure achieved by the inhibitor at different dosages. Successful completion of these studies will ready our lead compound for subsequent IND- enabling studies, to advance our lead molecule toward clinical utility as novel stroke therapy.

目标是开发有效治疗中风的新疗法。这将通过提供证据来实现，我们的先导化合物在大鼠中风模型中的体内活性以及支持性药代动力学和药效学（PK/PD）测定数据。我们已经确定了有效的和高度选择性的抑制剂的人类 12/15脂氧合酶，它通过破坏神经元，大脑的内皮细胞。我们现在想在缺血性中风的大鼠模型中测试我们的先导化合物，确定给药的最佳剂量和时间。将确定抑制剂的有效性通过测量梗死面积以及在存在或不存在12/15脂氧合酶的情况下由12/15脂氧合酶形成的酶产物，缺乏抑制剂。然后将这些结果与抑制剂达到的大脑暴露量相关联，不同的剂量这些研究的成功完成将使我们的先导化合物为后续的IND- 使研究，以推进我们的领导分子走向临床效用作为新的中风治疗。