替诺福韦前药设计合成及初步代谢

Design, Synthesis and Preliminary Metabolism of Tenofovir Prodrugs

摘要:

以替诺福韦（PMPA）为原料，经氨基保护，酰化，缩合，脱保护，成盐得到目标产物。共合成了八个化合物（Ⅲa～Ⅲh），收率为16.1%～40.7%。探讨了制备化合物Ⅱ时，不同碱性试剂对化合物Ⅰ转化率的影响；考察了乙酸与前药母体成盐比例问题。得到了最优化的实验条件为：碱性试剂选用三乙胺；乙酸与前药母体成盐物质的量之比为0.74～0.93∶1。得到的化合物经ESI-MS、1HNMR对化合物进行了结构表征。通过初步活性研究筛选出一个潜在化合物Ⅲh（替诺福韦二羟丙酮乙二醇缩酮酯），与富马酸替诺福韦二吡呋酯（TDF）相比，化合物Ⅲh体外大鼠和人血浆中稳定性分别提高了2倍和2.5倍。化合物Ⅲh在小鼠体内肝脏和肾脏中PMPA药时曲线下面积AUC(0-t)分别为(47314.75±10128.11)(μg•h)/L和(21670.64±8964.98) (μg•h)/L，而TDF在肝脏和肾脏中PMPA药时曲线下面积AUC(0-t)分别为(213269.79±10750.47) (μg•h)/L和(46379.24±3944.65)(μg•h)/L。该前药表现出一定的肝靶向性，并降低了肾毒性，具有一定的开发前景。

Abstract:

The target compounds were obtained through amino protection, acylation, condensation, deprotection and salification of tenofovir as the starting material, eight compounds were synthesized(Ⅲa～Ⅲh). The effect of different alkaline reagents on the conversion of compound Ⅰ during the preparation of compound Ⅱ and ratio of acetic acid to prodrug parent was studied. The optimal conditions were as following: Triethylamine was selected as the alkaline reagent; The molar ratio of acetic acid to prodrug parent was 0.74～0.93∶1. The structures of target products were confirmed by ESI-MS and 1HNMR. The synthesis method was simple and the yield of eight compounds was from 16.1% to 40.7%. A potential compound Ⅲh (tenofovir dihydroxyacetone ethylene ketal) was screened by preliminary activity study. Compared with tenofovir dipivoxil fumarate(TDF), the stability of compound Ⅲh in rat and human plasma in vitro were respectively increased by 2-fold and 2.5-fold. The live and kidney PMPA AUC(0-t) of compound Ⅲh in mice in vivo were respectively (47314.75±10128.11) (μg•h)/L and (21670.64±8964.98) (μg•h)/L while the AUC(0-t) of TDF were respectively (213269.79±10750.47) (μg•h)/L and (46379.24±3944.65) (μg•h)/L. This prodrug showed a certain liver targeting and low nephrotoxicity, which was worthy of further research.