Inhibitory effects of phthalimide derivatives on the activity of the hepatic cytochrome P450 monooxygenases CYP2C9 and CYP2C19
Inhibitory effects of phthalimide derivatives on the activity of the hepatic cytochrome P450 monooxygenases CYP2C9 and CYP2C19
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邻苯二甲酰亚胺衍生物对肝细胞色素P450单加氧酶CYP2C9和CYP2C19活性的抑制作用
DOI：
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发表时间：
2010
影响因子：
5.6
通讯作者：
K. Thurow
中科院分区：
文献类型：
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作者：
Üner Kolukisaoglu;C. Wendler;Dirk Goerdes;Annette Diener;K. Thurow
影响肝细胞色素（CYP）活性是药物相互作用的主要问题之一。因此，测试候选药物对这些酶的影响是早期药物发现的重要步骤。我们使用高通量抑制试验检测了480种内部邻苯二甲酰亚胺衍生物对不同CYP 450的抑制作用。在使用亚型CYP 2C 19的初始试验中，约57.5%的受试邻苯二甲酰亚胺衍生物显示出对该酶的显著增强的抑制作用。此外，发现对CYP 2C 9和CYP 2C 19的邻苯二甲酰亚胺抑制模式相似，而不相关的亚型CYP 2D 6和CYP 3A 4未受到特异性影响。此外，不到10%的随机选择的物质抑制CYP 2C 9。结构-功能关系分析表明，异吲哚环上氮原子上的取代基对CYP 2C 9/19的活性有重要影响。
Affecting hepatic cytochrome (CYP) activity is one of the major concerns in drug–drug interaction. Thus the testing of drug candidates on their impact on these enzymes is an essential step in early drug discovery. We tested a collection of 480 in-house phthalimide derivatives against different CYP450s using a high throughput inhibition assay. In initial tests with the isoform CYP2C19 about 57.5% of the tested phthalimide derivatives showed significantly enhanced inhibitory effects against this enzyme. In addition similar patterns of phthalimide inhibition for CYP2C9 and CYP2C19 were found, whereas the unrelated isoforms CYP2D6 and CYP3A4 were not specifically affected. Also less than 10% of randomly chosen substances inhibited CYP2C9. Analyses of structure-function relationships revealed that the substituent at the nitrogen atom in the isoindole ring is of crucial impact for the activity of CYP2C9/19.
杀菌剂克菌丹、敌菌丹、灭菌丹对大鼠肝脏及肝微粒体药物代谢酶系统影响的比较研究
DOI：
10.1111/j.1600-0773.1990.tb00739.x
发表时间：
1990
期刊：
Pharmacology & toxicology
影响因子：
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作者：
Dalvi,RR;Mutinga,ML
通讯作者：
Mutinga,ML