Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies
Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies
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DOI：
10.1016/j.bmc.2012.06.052
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发表时间：
2012-09-15
影响因子：
3.5
通讯作者：
Zimmermann, J.
中科院分区：
文献类型：
--
作者：
Atzrodt, J.;Blankenstein, J.;Zimmermann, J.
报道了稳定同位素标记的重要CYP亚型选择性探针内标物的合成，如睾酮1、双氯芬酸3、咪达唑仑5和右美沙芬7，以及它们相应的羟基化代谢产物6 β-羟基睾酮2，4 ′-羟基双氯芬酸4，1 ′-羟基咪达唑仑6和右啡烷8。应用酸、碱或均相和非均相过渡金属催化或其组合的微波增强的H/D交换反应被证明对于上述探针的直接氘标记是高效的。与传统的逐步合成方法相比，H/D交换和生物转化的组合提供了相当大的时间和成本节省的潜力，特别是对于4 '-羟基双氯芬酸4和1'-羟基咪达唑仑6的稳定同位素标记的内标物的合成。(C)2012爱思唯尔有限公司保留所有权利。
The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6 beta-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6. (C) 2012 Elsevier Ltd. All rights reserved.