帕拉米韦巯基二肽前药的合成及其稳定性研究

Synthesis and stability of peramivir mercapto dipeptide prodrugs

目的合成一系列帕拉米韦巯基二肽前药并考察其在不同介质中的稳定性。方法以帕拉米韦结构中1位羧基为反应位点,巯基二肽为载体,通过酯化反应合成一系列帕拉米韦巯基二肽前药。采用高效液相色谱法测定帕拉米韦巯基二肽前药在不同pH值缓冲溶液、大鼠胃液、大鼠小肠液、人工胃液(含胃蛋白酶)、人工肠液(含胰酶)、大鼠血浆中的稳定性,采用一级动力学方程计算降解速率常数。结果合成了4个帕拉米韦巯基二肽前药,它们在胃肠道中稳定性良好。结论帕拉米韦巯基二肽前药具有良好的稳定性,为帕拉米韦口服给药的开发可提供依据。

Objective To synthesize a series of peramivir mercapto dipeptide prodrugs and investigate their stability at the different medium.Methods A series of prodrugs of peramivir were synthesized by esterification with 1 carboxyl group in the structure of peramivir as the reaction site and phobic dipeptide as the carrier.The stability of peramivir merapto dipeptide prodrug in different pH buffer solutions,rat gastric juice,rat small intestinal juice,artificial gastric juice(containing pepsin),artificial intestinal juice(containing pancreatin),and rat plasma were determined by HPLC method.First-order kinetic equations were used to calculate the degradation rate constant.Results Four peramivir mercapto dipeptide prodrugs were synthesized with good stability at the different medium.Conclusion Peramivir mercapto dipeptide prodrugs have good stability,which can provide a basis for the development of peramivir oral administration.