Phenylpropanoid Analogs 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，因为溶栓与 组织纤溶酶原激活剂（tPA）已被FDA批准。然而，tPA的利用是有限的 治疗窗短，脑出血风险增加。因为有必要 安全和有效的中风治疗，我们集中精力合成，识别和开发新的 神经保护药物的种类。我们有大量的体外和体内中风的初步证据 模型表明，苯丙素或多酚家族的化合物，其中包括（1） 绿原酸;（2）非瑟酮;和（3）黄芩素，可用于治疗中风。对于这种转化药物 开发计划，我们将使用一个筛选漏斗，包括体外和体内的组合， 有效开发属于所述化合物家族的新的临床候选物 以上首先，我们将创建一个集中的多样性库，该库涵盖了基因组上许多可能的替换位置。 绿原酸、非瑟酮和黄芩素的母体骨架（支架）。新的分子将被筛选 使用两种体外中风试验，使我们能够选择最好和最“活性”的化合物进行测试 采用家兔体内小凝块栓塞模型（RSCEM），建立tPA所用的脑卒中模型。 我们将在体内筛选化合物，以选择显著改善临床评分的候选化合物 治疗时间窗很长一旦我们确定了候选药物，我们将评估药代动力学， 本发明还将研究化合物的毒性特征，并且还将研究施用新化合物的效果。 神经保护剂与tPA组合以选择患者群体并确定是否存在神经保护剂。 化合物与tPA组合可具有有益效果。当最终候选人被选中时， 将使用GMP批准的设施合成药物用于临床试验，将提交IND并进行临床试验。 审判将开始。总的来说，我们将确定一种新的神经保护化合物， 脑屏障，改善兔栓塞性中风后的临床评分，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。

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.