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目的改进PSI-6130药动学特性,发现新的抗丙型肝炎病毒(HCV)药物。方法基于合理的前药设计理论,利用多步合成手段合成PSI-6130前药。通过测定大鼠口服PSI-6130前药后血浆中PSI-6130暴露程度,评价PSI-6130前药在体内代谢转化为PSI-6130的效率。结果与结论合成了5个PSI-6130前药,其结构经MS、1 H-NMR和13 C-NMR谱确证,纯度采用HPLC法测定;PSI-6130前药在大鼠体内转化实验结果显示,5个前药的PSI-6130口服生物利用度都有大幅提高,提高了原药的口服生物利用度,为进一步研究奠定了基础。
Objective To improve the pharmacokinetics of PSI-6130 and to find novel anti-hepatitis C virus (HCV) drugs. Methods Based on rational prodrug design theory, PSI-6130 prodrug was synthesized by multi-step synthesis. The efficiency of PSI-6130 prodrugs in vivo metabolized to PSI-6130 was evaluated by measuring the extent of plasma PSI-6130 exposure in rats after oral administration of PSI-6130 prodrugs. RESULTS AND CONCLUSIONS Five PSI-6130 prodrugs were synthesized and their structures were confirmed by MS, 1 H-NMR and 13 C-NMR spectra. The purity of PSI-6130 prodrug was determined by HPLC. The five bioactives of PSI-6130 of five prodrugs all increased greatly, which improved the oral bioavailability of the prodrug and laid the foundation for further research.