Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1.
Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1.
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DOI：
10.1016/j.bmcl.2018.02.035
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发表时间：
2018-04
影响因子：
2.7
通讯作者：
Masato Takahashi;T. Ogawa;H. Kashiwagi;F. Fukushima;Misaki Yoshitsugu;M. Haba;M. Hosokawa
中科院分区：
文献类型：
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作者：
Masato Takahashi;T. Ogawa;H. Kashiwagi;F. Fukushima;Misaki Yoshitsugu;M. Haba;M. Hosokawa
有必要考虑前药对代谢酶的亲和力，以有效激活体内的前药。虽然已经考虑到这些化学性质合成了许多前药，但是考虑到诸如代谢酶的底物识别能力的生物性质的结构设计的研究很少。在这份报告中，化学合成和评价吲哚美辛前药代谢激活的人羧酸酯酶1（hCES 1）。将合成的前药在人肝微粒体（HLM）、人肠微粒体（HIM）和hCES 1的溶液中进行水解反应，并考察水解参数，以评价这些前药的水解速率并阐明hCES 1的底物识别能力。结果表明，在HLM、HIM和hCES 1溶液中，水解速率随酯的空间位阻和立体化学性质而变化。此外，在hCES 1催化的水解反应中，反应活性高的硫代正丁酯的Vmax值明显低于正丁酯的Vmax值。
It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described. The synthesized prodrugs were subjected to hydrolysis reactions in solutions of human liver microsomes (HLM), human intestine microsomes (HIM) and hCES1, and the hydrolytic parameters were investigated to evaluate the hydrolytic rates of these prodrugs and to elucidate the substrate recognition ability of hCES1. It was found that the hydrolytic rates greatly change depending on the steric hindrance and stereochemistry of the ester in HLM, HIM and hCES1 solutions. Furthermore, in a hydrolysis reaction catalyzed by hCES1, the Vmaxvalue ofn-butyl thioester with chemically high reactivity was significantly lower than that ofn-butyl ester.