Phenylpropanoid Analogs to Treat Stroke

治疗中风的苯丙素类似物

基本信息

批准号：
7943150
负责人：
Paul A Lapchak
金额：
$ 90.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943150
关键词：
Acute Adenosine Triphosphate Adverse drug effect Alteplase Animal Model Antioxidants Apoptosis Applications Grants Arachidonate 15-Lipoxygenase Behavior Behavioral Biological Assay Blood Blood - brain barrier anatomy Blood Clot Blood Vessels Blood coagulation Brain Edema Brain Injuries Cell Survival Cells Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrovascular Circulation Cerebrum Cessation of life Chemicals Chlorogenic Acid Clinical Clinical Investigator Clinical Trials Coagulation Process Collection Coupled Cytochrome P450 Development Diversity Library Dose Drug Kinetics Embolism Emergency Care Ensure Enzymes Esters Family Flavonoids Free Radical Scavenging Functional disorder Glutathione Hour In Vitro Infarction Injury Intravenous Investigation Ischemia Ischemic Stroke Libraries Lipoxygenase Inhibitors MDCK cell Matrix Metalloproteinase Inhibitor Measures Methods Middle Cerebral Artery Occlusion Modeling Monitor Nerve Degeneration Neurologic Dysfunctions Neurons Neuroprotective Agents Oryctolagus cuniculus Parents Patients Penetration Peroxides Pharmaceutical Preparations Phase Positioning Attribute Primary carcinoma of the liver cells Rattus Reactive Oxygen Species Recombinants Risk Risk Assessment Role Safety Screening procedure Series Staining method Stains Stroke Sulfhydryl Compounds Testing Therapeutic Therapeutic Embolization Time Tissues Toxic effect Treatment Protocols United States Food and Drug Administration Vertebral column analog baicalein base design drug candidate drug development drug testing excitotoxicity fisetin improved in vitro testing in vivo ischemic lesion neuroprotection novel patient population polyphenol pre-clinical programs response scaffold small molecule thrombolysis

项目摘要

Acute ischemic stroke resulting from an embolism is now a treatable condition, because thrombolysis with tissue plasminogen activator (tPA) has been approved by the FDA. However, the utilization of tPA is limited by its short therapeutic window and increased risk of intracerebral hemorrhage. Because there is a need for safe and effective stroke treatments, we have concentrated on synthesizing, identifying'and developing novel classes of neuroprotective drugs. We have extensive preliminary evidence from in vitro and in vivo stroke models suggesting that the phenylpropanoid or polyphenol family of compounds, which includes (1) Chlorogenic acid; (2) Fisetin; and (3) Baicalein, may be useful to treat stroke. For this translational drug development program, we will use a screening funnel consisting of a combination of in vitro and in vivo stroke models to effectively develop new clinical candidates belonging to the family of compounds described above. First, we will create a focused diversity library that covers many possible substitution positions on the parent backbone (scaffold) of chlorogenic acid, fisetin and baicalein. The new molecules will be screened using two in vitro stroke assays to allow us to select the best and most "active" compounds to be tested in vivo using the rabbit small clot embolism model (RSCEM), the stroke model used in the development of tPA. We will screen the compounds in vivo to select candidates that significantly improve clinical rating scores with long therapeutic windows. Once we have identified candidates, we will assess the pharmacokinetic and toxicity profiles of the compounds, and will also study the effects of administration of the novel neuroprotective agents in combination with tPA to select a patient population and determine if the compounds may have beneficial effects in combination with tPA. When the final candidate is selected, the drug will be synthesized for a clinical trial using a GMP-approved facility, an IND will be filed and a clinical trial will be initiated. Overall, we will identify a new neuroprotective compound that readily crosses the blood brain barrier, improves clinical rating scores following embolic strokes in rabbits and has a clean safety profile so that the neuroprotective compound can be developed to treat stroke.

栓塞引起的急性缺血性中风现在是一种可治疗的疾病，因为与 FDA已批准组织纤溶酶原活化剂（TPA）。但是，TPA的利用率有限通过短暂的治疗窗口和脑出血的风险增加。因为有必要安全有效的中风治疗，我们集中于合成，识别“开发新颖的新颖” 神经保护药物类别。我们有来自体外和体内中风的广泛初步证据模型表明苯基丙烷类或多酚家族包括（1）绿原酸；（2）Fisetin; （3）黄氨酸可能对治疗中风很有用。对于这种翻译药物开发计划，我们将使用由体外和体内组合组合的筛选漏斗中风模型有效地开发了属于描述化合物家族的新临床候选者多于。首先，我们将创建一个集中的多样性库，涵盖许多可能的替代立场绿原酸，fisetin和黄酸酯的母体骨架（支架）。新分子将被筛选使用两种体外中风测定法，使我们能够选择最佳和最“活跃”的化合物。使用兔子小凝块栓塞模型（RSCEM）的体内，这是用于TPA开发的中风模型。我们将在体内筛选化合物，以选择显着提高临床评分的候选者带有长期治疗的窗户。一旦确定了候选人，我们将评估药代动力学和化合物的毒性谱，还将研究新型给药的影响神经保护剂与TPA联合选择患者群体，并确定是否是否化合物与TPA结合使用可能具有有益的作用。选择最终候选人时，将使用GMP批准的设施合成药物进行临床试验，将提交IND并进行临床试验将开始。总体而言，我们将确定一种新的神经保护化合物，容易跨过血液脑屏障，改善兔子栓塞性衰减后的临床评分，并具有干净的安全性曲线，以便可以开发神经保护化合物来治疗中风。