Novel 12/15 lipoxygenase inhibitors for the treatment of stroke

用于治疗中风的新型 12/15 脂氧合酶抑制剂

基本信息

批准号：
8846695
负责人：
KLAUS VAN LEYEN
金额：
$ 27.31万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846695
关键词：
ALOX15 gene Adjuvant Affinity Alteplase Animals Arachidonate 15-Lipoxygenase Behavioral Biological Assay Blood - brain barrier anatomy Brain Brain Injuries CYP2D6 gene CYP3A4 gene Cause of Death Cell Death Cells Cerebral Ischemia Characteristics Cultured Cells Dose Drug Kinetics Endothelial Cells Enzymes Extravasation Female Gender Glutamates Goals Health Hemorrhage Hippocampus (Brain)Hour Human In Vitro Infarction Ischemia Ischemic Stroke Knock-out LOX gene Laboratories Ligands Lipoxygenase Inhibitors Metabolic Microsomes Middle Cerebral Artery Occlusion Modeling Morbidity - disease rate Mus Neurons Neuroprotective Agents Outcome Study Oxidative Stress PTGS2 gene Penetrance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Process Property Prostaglandin-Endoperoxide Synthase Protein Isoforms Solubility Source Stroke System Testing Therapeutic Thrombosis Thrombotic Stroke Time United States aqueous base chemical synthesis clinical application cyclooxygenase 1 design disability drug discovery improved in vivo inhibitor/antagonist intravenous administration male mortality mouse model neuron loss neuroprotection news novel novel therapeutics protective effect research study screening stroke therapy thrombolysis

项目摘要

DESCRIPTION (provided by applicant): The goal is to develop novel therapeutics effective in stroke. This will be achieved by advancing candidate molecules toward clinical application utilizing our assay cascade to identify novel, selective inhibitors of the 12/15 lipoxygenase that protect against ischemic stroke. Our drug discovery approach will be to synthesize novel ligands based on the LOXBlock inhibitors that are potent inhibitors of the human 12/15 lipoxygenase and that protect neurons against oxidative stress-related cell death. Candidate molecules will undergo profiling to assess criteria specifically related to the physicochemical properties of compounds in a therapeutic setting, including enzyme selectivity and tests to determine potential interactions with key metabolic enzyme systems. Best candidates will be tested for protection against experimental stroke in mice.

描述（由申请人提供）：目标是开发有效治疗中风的新型疗法。这将通过利用我们的检测级联将候选分子推进临床应用来实现，以识别可预防缺血性中风的新型选择性 12/15 脂氧合酶抑制剂。我们的药物发现方法将是合成基于 LOXBlock 抑制剂的新型配体，这些抑制剂是人类 12/15 脂氧合酶的有效抑制剂，可保护神经元免受氧化应激相关的细胞死亡。候选分子将进行分析，以评估与治疗环境中化合物的理化性质特别相关的标准，包括酶选择性和测试以确定与关键代谢酶系统的潜在相互作用。最好的候选者将在小鼠身上进行针对实验性中风的保护作用测试。