Screening candidate anticancer drugs for brain tumor chemotherapy: pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues.
Screening candidate anticancer drugs for brain tumor chemotherapy: pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues.
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DOI：
10.1007/s10637-012-9806-x
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发表时间：
2012-12
影响因子：
3.4
通讯作者：
Gallo, James M.
中科院分区：
文献类型：
--
作者：
Lv, Hua;Wang, Fan;Reddy, M. V. Ramana;Zhou, Qingyu;Zhang, Xiaoping;Reddy, E. Premkumar;Gallo, James M.
采用药物动力学[PK]驱动的筛选过程，从141个化合物组成的一系列低分子抗癌药物[ON27x]中筛选新的脑肿瘤化疗药物。筛选程序结合了硅胶、体外和体内小鼠研究，这些研究被分成一系列第一级和第二级故障，导致在携带脑瘤的小鼠身上进行了两种类似物的最终研究。一级失败包括分子量为>；450 Da的药物，预测的对数P(LogP)为<；2或>；3.5，以及细胞毒性IC50值为>；2um。接下来，18种化合物在正常小鼠身上进行了盒式剂量研究，确定了具有高系统清晰度和低血脑屏障[BBB]渗透率的化合物。这些指数连同一个被称为大脑暴露指数的衍生参数，包括导致两种化合物[ON27570，ON27740]作为单一药物[离散剂量]给带有脑内肿瘤的小鼠的二级失败。ON27570‘S的结果PK参数与盒式给药格式中获得的参数比较表明，药物-药物相互作用最有可能发生在血脑屏障转运水平，并促使使用体外MDCK-MDR1转运模型来帮助评估差异的性质。总体而言，该方法能够确定具有合适PK特征的候选化合物，但对该方法的进一步修订，如使用体外代谢和转运试验，可能会改进PK指导的方法，以确定脑瘤化疗的有效药物。
A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico, in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of > 450 Da, a predicted log P (log P) of either < 2 or > 3.5, and a cytotoxicity IC50 value of > 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood-brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570’s resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy.
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影响因子：
4.9
作者：
Luo, Shuanghui;Kansara, Viral S.;Mitra, Ashim K.
通讯作者：
Mitra, Ashim K.
DOI：
10.2174/138620708783877717
发表时间：
2008-03-01
影响因子：
1.8
作者：
Carlson, Timothy J.;Fisher, Michael B.
通讯作者：
Fisher, Michael B.
影响因子：
3.8
作者：
BOUDINOT, FD;JUSKO, WJ
通讯作者：
JUSKO, WJ
影响因子：
3
作者：
Smith, NF;Hayes, A;Workman, P
通讯作者：
Workman, P
影响因子：
8.8
作者：
Lemos, C.;Kathmann, I.;Giovannetti, E.;Calhau, C.;Jansen, G.;Peters, G. J.
通讯作者：
Peters, G. J.