治疗急性缺血性中风(AIS)的新型神经保护性化合物的开发一直存在问题且相当复杂,由于许多经过临床测试的候选人缺乏明显的多效性活性,无法有效地穿过血脑屏障(BBB),生物利用度差或有毒。此外,使用标准行为终点测量的化合物没有赋予显著的神经保护或临床疗效,在异质性中风患者人群的临床试验中进行研究。为了规避上述的一些药物开发问题,我们使用合理的漏斗方法来识别和培养有前途的候选人。使用逐步的方法,我们已经根据两种不同的神经保护试验确定了一系列化合物。然后,我们选择了候选人并确定了他们的“类似药物”属性。本指南文章详细介绍了用于显示一系列新型化合物的多效性活性的体外筛选测定;包括与母体化合物非塞丁相比增强的神经保护活性。此外,在开发过程中进行初步的药物去风险或风险降低,我们在CeeTox试验中使用了化合物评估,ADME毒性使用AMES测试遗传毒性和与细胞色素P450的相互作用,使用CYP450抑制分析CYP450酶谱(CYP1A2,CYP2C9,CYP2C19,CYP2D6和CYP3A4)作为药物相互作用的量度。此外,已经使用转染的MadinDarby犬肾(MDCK)细胞测定法研究了化合物以评估血脑屏障穿透(BBB)。使用这一系列的检测方法,我们已经确定了4个新的分子作为AIS治疗的发展。
The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their \"drug-like\" properties. This
guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment.