恩曲他滨磷酰胺酯类衍生物的合成及初步抗HBV活性  

Synthesis and in vivo Anti-hepatitis B Virus Activity of Emtricitabine Phosphoramidate Analogues

作　　者：平晓晴 徐宏江 胡志[1] 赵烨[1] 杨玉雷[1] PING Xiaoqing;XU Hongjiang;HU Zhi;ZHAO Ye;YANG Yulei(Shanghai Institute of Pharmaceutical Industry, Shanghai 201203;Zhengda Tianqing Pharmaceutical Group Co., Ltd., Nanjing 210042)

机构地区：[1]中国医药工业研究总院上海医药工业研究院,上海201203 [2]正大天晴药业集团有限公司,江苏南京210042

出　　处：《中国医药工业杂志》2018年第5期581-588,共8页Chinese Journal of Pharmaceuticals

摘　　要：磷酰胺酯前药是近年来核苷类药物结构修饰的一个重要方向,本文以恩曲他滨为底物,运用磷酰胺酯前药策略和ProTide技术对恩曲他滨5'-OH进行磷酰胺酯化修饰,设计并合成了11个恩曲他滨磷酰胺酯类新化合物,并经~1H NMR、MS确证结构。以恩曲他滨作为对照,进行了体外稳定性评价,筛选出5个稳定性较好的化合物(103Nb、104Na、107Na、109Na和113Nb),并对其进行了乙肝模型鸭中的药代动力学评价及抗HBV活性研究,测试结果显示化合物104Na、107Na和109Na对DHBV-DNA拷贝数下降倍数均高于母药,其中109Na对DHBV-DNA拷贝数下降倍数比母药提高了近一倍,具有潜在的提高恩曲他滨药效的可能。Phosphoramidate prodrug is an increasingly important direction of nucleoside modifications. In order to enhance therapeutic effect of emtricitabine, eleven emtricitabine phosphoramidate analogues were synthesized using ProTide strategies, and all of them have been characterized by ^1H NMR and MS. The stability experiments in vitro were completed, from which five compounds were selected for further pharmacodynamics and anti-HBV pharmacokinetics experiments in vivo. The results indicated that the compounds including 104Na, 107Na and 109Na showed good effect in decreasing DHBV-DNA copy number compared with their prodrug emtricitabine. And the DHBV-DNA copy number of compound 109Na was decreased twice than emtricitabine, which indicated that compound 109Na would be worthy of further study.

关 键 词：恩曲他滨 前药 磷酰胺酯 抗HBV活性 合成 

分 类 号：R978.7[医药卫生—药品] R914.5[医药卫生—药学]