Phenylpropanoid Analogs to Treat Stroke

描述(由申请人提供)： 由于组织型纤溶酶原激活剂(TPA)溶栓疗法已被FDA批准，因此血栓栓塞症引起的急性缺血性中风现在是一种可以治疗的疾病。然而，tPA的治疗窗口短，脑出血风险增加，限制了tPA的应用。由于需要安全和有效的中风治疗，我们专注于合成、识别和开发新型神经保护药物。我们有大量来自体外和体内中风模型的初步证据表明，苯丙烷或多酚类化合物家族，包括(1)绿原酸；(2)菲斯汀；(3)黄芩素，可能对治疗中风有用。对于这一转化型药物开发计划，我们将使用由体外和体内卒中模型相结合的筛选漏斗来有效地开发属于上述化合物家族的新的临床候选药物。首先，我们将创建一个集中的多样性文库，该文库涵盖绿原酸、非瑟素和黄芩素的亲本骨架(支架)上的许多可能的替代位置。新分子将使用两种体外中风试验进行筛选，以使我们能够选择最好和最“活跃”的化合物，并使用兔小血栓栓塞症模型(RSCEM)进行体内测试，RSCEM是开发tPA的中风模型。我们将在体内筛选化合物，以选择具有较长治疗窗口的显著提高临床评分的候选药物。一旦我们确定了候选药物，我们将评估这些化合物的药代动力学和毒性特征，并将研究新型神经保护剂与tPA联合使用的效果，以选择患者群体，并确定这些化合物与tPA联合使用是否具有有益效果。当最终候选药物被选中时，该药物将被合成用于临床试验，使用GMP批准的设施，将提交IND，并将启动临床试验。总体而言，我们将确定一种新的神经保护化合物，它可以很容易地穿过血脑屏障，提高兔栓塞性中风后的临床评分，并具有干净的安全性，从而可以开发出用于治疗中风的神经保护化合物。 相关性：我们将使用由体外和体内卒中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对象。这种新的神经保护化合物很容易通过血脑屏障，并在兔栓塞性中风后的较长治疗窗口内改善临床评分，将进一步开发用于治疗中风。

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.