Phenylpropanoid Analogs to Treat Stroke

治疗中风的苯丙素类似物

• 批准号: 7922173
• 负责人: Paul A Lapchak
• 金额: $ 122.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922173
• 关键词: Phenylpropanoid; Analogs; Treat; Stroke

DESCRIPTION (provided by applicant): 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. RELEVANCE: We will use a screening funnel consisting of in vitro and in vivo stroke models to effectively identify, optimize and develop new clinical candidates. The new neuroprotective compound that readily crosses the BBB and improves clinical rating scores with a long therapeutic window following embolic strokes in rabbits will further be developed to treat stroke.

描述（由申请人提供）： 栓塞引起的急性缺血性中风现在是一种可治疗的疾病，因为通过FDA批准了用组织纤溶酶原激活剂（TPA）溶栓。但是，TPA的利用受到其短窗口窗口的限制，并增加了脑出血的风险。由于需要安全有效的中风治疗，因此我们专注于合成，识别和开发新型的神经保护药物。我们有来自体外和体内卒中模型的广泛初步证据，表明苯基丙烷或多酚家族的化合物包括（1）氯化酸； （2）Fisetin; （3）黄氨酸可能对治疗中风很有用。对于这个翻译药物开发计划，我们将使用由体外和体内卒中模型组合组成的筛查漏斗，以有效地开发出上述化合物家族的新临床候选者。首先，我们将创建一个集中的多样性文库，该文库涵盖了绿原酸，Fisetin和Baicalein的母体骨架（支架）上许多可能的替代位置。新分子将使用两个体外中风测定法筛选，以使我们能够使用兔子小凝块栓塞模型（RSCEM）选择最佳和最“活跃”的化合物，这是TPA开发中使用的中风模型。我们将在体内筛选化合物，以选择可通过长期治疗窗口显着提高临床评分得分的候选者。一旦确定了候选者，我们将评估化合物的药代动力学和毒性谱，还将研究新型神经保护剂与TPA结合使用的施用，以选择患者群体，并确定这些化合物在与TPA结合使用时是否具有有益的作用。选择最终候选者时，将使用GMP批准的设施合成该药物作​​为临床试验，将提交IND并开始临床试验。总体而言，我们将确定一种新的神经保护化合物，该化合物很容易跨越血脑屏障，在兔子中栓塞性栓塞后提高了临床评分评分，并具有清洁的安全性，因此可以开发神经保护化合物来治疗中风。 相关性：我们将使用由体外和体内中风模型组成的筛选漏斗来有效地识别，优化和开发新的临床候选者。新的神经保护化合物很容易跨越BBB并通过较长的治疗窗口改进兔子中风后的临床评分得分，以治疗中风。