Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules.
Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules.
复制标题
DOI：
10.1007/s12975-012-0200-y
复制
发表时间：
2013-06
影响因子：
6.9
通讯作者：
Lapchak, Paul A.
中科院分区：
文献类型：
--
作者：
Lapchak, Paul A.
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是有问题的并且相当复杂，因为许多已经在临床上测试的候选物缺乏显著的多效性活性，不能有效地穿过血脑屏障（BBB），具有差的生物利用度或有毒。此外，当在中风患者的异质群体中进行临床试验研究时，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功效。为了避免上述药物开发问题，我们使用了合理的漏斗方法来识别和开发有前途的候选药物。使用逐步的方法，我们已经确定了一系列化合物的基础上两个不同的神经保护试验。然后，我们已经采取了候选人，并确定其“药物样”的属性。这篇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试验;包括与母体化合物非瑟酮相比增强的神经保护活性。此外，对于开发期间的初步药物风险降低或风险降低，我们使用CeeTox试验中的化合物评估、ADME毒性（使用艾姆斯试验进行遗传毒性检测）和与细胞色素P450的相互作用（使用针对CYP 450酶谱（CYP 1A 2、CYP 2C 9、CYP 2C 19、CYP 2D 6和CYP 3A 4）的CYP 450抑制分析）作为药物相互作用的指标。此外，已经使用转染的Madin达比犬肾（MDCK）细胞测定来研究化合物以评估血脑屏障穿透（BBB）。使用这一系列的测定，我们已经鉴定了4种新的分子被开发作为AIS治疗。
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.
登录
查看更多内容
DOI：
10.1073/pnas.70.3.782
发表时间：
1973-01-01
影响因子：
11.1
作者：
AMES, BN;LEE, FD;DURSTON, WE
通讯作者：
DURSTON, WE
DOI：
10.1073/pnas.70.8.2281
发表时间：
1973-01-01
影响因子：
11.1
作者：
AMES, BN;DURSTON, WE;LEE, FD
通讯作者：
LEE, FD
影响因子：
2.9
作者：
GRIFFITH, OW
通讯作者：
GRIFFITH, OW
影响因子：
158.5
作者：
Hacke, Werner;Kaste, Markku;Toni, Danilo
通讯作者：
Toni, Danilo
影响因子：
7.3
作者：
Chiruta, Chandramouli;Schubert, David;Dargusch, Richard;Maher, Pamela
通讯作者：
Maher, Pamela