Phenylpropanoid Analogs to Treat Stroke

栓塞导致的急性缺血性中风现在是一种可以治疗的情况，因为溶栓治疗 组织型纤溶酶原激活剂(TPA)已被FDA批准。然而，tPA的利用是有限的。 治疗窗口期短，脑出血风险增加。因为有必要 安全有效的中风治疗，我们专注于合成、识别和开发新的 神经保护性药物的类别。我们有大量来自体外和体内中风的初步证据 模型表明苯丙烷类或多酚类化合物，包括(1) 绿原酸；(2)菲斯汀；(3)黄芩素，可能对治疗中风有用。这种转化性药物 开发计划，我们将使用由体外和体内相结合的筛选漏斗 中风模型有效地开发属于所述化合物家族的新的临床候选对象 上面。首先，我们将创建一个有重点的多样性文库，该文库涵盖了 绿原酸、鱼腥草素和黄芩素的亲本骨架(支架)。新的分子将被筛选出来 使用两种体外中风测试，让我们能够选择最好和最“活跃”的化合物进行测试 体内采用兔小块血栓栓塞症模型(RSCEM)，采用卒中模型发展tPA。 我们将在体内筛选化合物，以选择显著提高临床评分的候选化合物 有很长的治疗窗口。一旦我们确定了候选药物，我们将评估其药代动力学和 这些化合物的毒性分布，并将研究给药的效果 神经保护剂与tPA相结合来选择患者群体并确定 化合物与tPA联合使用可能有有益的效果。当最终候选人被选中时， 药物将使用GMP批准的设施合成用于临床试验，IND将提交，临床试验将 审判将会启动。总体而言，我们将确定一种新的神经保护化合物，它很容易通过血液。 脑屏障，改善兔栓塞性中风后的临床评分，具有清洁的安全性 这样，这种神经保护化合物就可以被开发出来用于治疗中风。

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.