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  

Design, synthesis and pharmacokinetic study of monocylic β lactam aztreonam prodrugs

作　　者：郭志浩 张昕彤 卢曦[1] 陈阳[1] 宋丹青[1] 李迎红[1] 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)

机构地区：[1]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

出　　处：《药学学报》2021年第11期3104-3111,共8页Acta Pharmaceutica Sinica

基　　金：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)。

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Clog P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。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.

关 键 词：氨曲南 ClogP 前药 酶解速率 种属差异 

分 类 号：R914[医药卫生—药物化学]