药学学报, 2021, 56(11): 3104-3111
引用本文:
郭志浩, 张昕彤, 卢曦, 陈阳, 宋丹青, 李迎红*. 单环β内酰胺抗生素氨曲南前药的设计合成与药代动力学研究[J]. 药学学报, 2021, 56(11): 3104-3111.
GUO Zhi-hao, ZHANG Xin-tong, LU Xi, CHEN Yang, SONG Dan-qing, LI Ying-hong*. Design, synthesis and pharmacokinetic study of monocylic β lactam aztreonam prodrugs[J]. Acta Pharmaceutica Sinica, 2021, 56(11): 3104-3111.

单环β内酰胺抗生素氨曲南前药的设计合成与药代动力学研究
郭志浩, 张昕彤, 卢曦, 陈阳, 宋丹青, 李迎红*
中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
摘要:
本研究设计合成了9个氨曲南羧酸酯前药,对其测定了不同种属动物血浆中的代谢稳定性,包括大鼠、小鼠、犬、猴和人血浆。结果表明,氨曲南羧酸酯对不同血浆酯酶的敏感性存在种属差异,在啮齿类动物血浆中的酶解速率远远高于非啮齿类;在人血浆中的酶解速率可能与化合物本身的ClogP值呈正相关。该研究结果为单环β内酰胺抗生素前药的研发提供了有益的指导。
关键词:    氨曲南      ClogP      前药      酶解速率      种属差异     
Design, synthesis and pharmacokinetic study of monocylic β lactam aztreonam prodrugs
GUO Zhi-hao, ZHANG Xin-tong, LU Xi, CHEN Yang, SONG Dan-qing, LI Ying-hong*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
In this study, 9 aztreonam prodrug compounds were designed and synthesized, and their metabolic stability in plasmas of different species (rat, mouse, dog, monkey and human) were evaluated. Species differences were observed in aztreonam carboxylates's sensitivity to the plasma esterases among different species, and the hydrolysis rates of aztreonam carboxylates in rodent plasmas were much higher than in non-rodent plasmas. Moreover, the hydrolysis rates of aztreonam carboxylates might be positively correlated with the ClogP values in human plasma. These results provide useful guidance for the further development of monocyclic β lactam prodrugs.
Key words:    aztreonam    ClogP    prodrug    hydrolysis rate    species difference   
收稿日期: 2021-06-15
DOI: 10.16438/j.0513-4870.2021-0867
基金项目: 国家十三五科技重大专项(2019ZX09721001);中国医学科学院医学与健康科技创新工程资助项目(2017-12M-1-012).
通讯作者: 李迎红,Tel:86-10-63033012,Fax:86-10-63165268,E-mail:liyinghong@imb.pumc.edu.cn
Email: liyinghong@imb.pumc.edu.cn
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