Development of human 12/15-lipoxygenase therapeutics for stroke

开发人类 12/15-脂氧合酶治疗中风的药物

基本信息

批准号：
9898504
负责人：
KLAUS VAN LEYEN
金额：
$ 66.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898504
关键词：
12-HETE Adjuvant Alteplase Arachidonate 15-Lipoxygenase Biological Assay Brain Brain hemorrhage Cause of Death Cell Death Cells Cerebral hemisphere hemorrhage Cerebrovascular system Collaborations Development Direct Costs Dose Edema Eicosanoids Enzymatic Biochemistry Enzymes FDA approved Female Filament Formulation Goals Hemorrhage Hepatocyte Human In Vitro Infarction Injury Ischemia Ischemic Stroke Lead Ligands Lipoxygenase Measures Metabolic Modeling Morbidity - disease rate Mus Neurologic Neurons Oryctolagus cuniculus Oxidative Stress Patients Pharmaceutical Chemistry Pharmacotherapy Property Prostaglandin-Endoperoxide Synthase Public Health Recording of previous events Reperfusion Therapy Rodent Solubility Stents Stroke Structure-Activity Relationship System Testing Therapeutic Time Treatment Efficacy United States aged aqueous base behavioral outcome clinical application clinically relevant drug discovery effective therapy efficacy testing embolic stroke enzyme activity improved improved outcome in vivo in vivo evaluation inhibitor/antagonist intravenous administration lead optimization mortality mouse model multimodality neuron loss novel novel therapeutics pharmacokinetics and pharmacodynamics phase 1 testing programs safety study scaffold scale up side effect stroke model stroke patient stroke therapy thrombolysis

项目摘要

Summary 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 ML351 scaffold 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 evaluated in a battery of tests for protection against experimental stroke in mice and rabbits.

概括目的是开发有效的中风的新型治疗剂。这将通过前进来实现利用我们的测定级联鉴定新颖的候选分子，用于临床应用预防缺血性中风的12/15脂氧酶的选择性抑制剂。我们的药物发现方法将是根据ML351脚手架合成新型配体的方法人类12/15脂氧酶的有效抑制剂，并保护神经元免受氧化的影响与压力相关的细胞死亡。候选分子将进行分析以评估标准与治疗环境中化合物的理化特性特别相关，包括酶选择性和测试以确定与关键代谢的潜在相互作用酶系统。最好的候选人将在一系列测试中评估以防止小鼠和兔子的实验中风。