基于酯酶和UGT酶双靶点程序化水解的他喷他多口服前药的设计与评价

含有酚羟基的化合物在口服经过肠道和肝脏时在羟基位置上易发生二相代谢反应，形成结合型代谢物，导致其口服生物利用度低且个体差异大，因此急需解决这类口服药物共性问题的策略。他喷他多是一种新型的口服中枢作用镇痛药，在肝脏经UDP-葡萄糖苷酸转移酶(UGT)1A9和UGT2B7代谢酶介导的葡糖苷酸化消除，广泛的首过效应导致了其较低的生物利用度(约32%)。本课题以他喷他多为研究对象，针对UGT所代谢的酚羟基位点进行结构修饰，构建基于肝脏酯酶和UGT酶双靶点程序化水解的氨基甲酸酯型前药；通过调节酯键区域空间位阻来操控前药的水解速度及程度；从酯酶和UGT酶代谢稳定性以及镇痛药效筛选等方面对前药进行考察和筛选；结合药物理化和结构参数，建立定量结构-代谢稳定性关系，指导前药的合理设计。本项目的研究成果为提高首过效应强且具有酚羟基结构特征的药物的口服生物利用度提供了一种共性的解决策略。

Chemical compounds containing phenolic hydroxyl group can be metabolized by phase II conjugation reaction in the gastrointestinal tract and liver when they are given orally, resulting in low bioavailability and significant individual differences. Therefore, the strategy to solve the common problems of such drugs is urgently needed. Tapentadol is a novel oral analgesic which combines μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. The main metabolism pathway of tapentadol is direct glucuronidation (phase II metabolism) to form tapentadol-O-glucuroide in all species investigated. However with a remarkable first-pass effect, the bioavailability of tapentadol is only 32% in human. A series of carbamate ester prodrug of tapentadol are designed and synthesized to improve the metabolic stability and thus the oral bioavailability in this study. The carbamate functional groups are introduced to the phenolic hydroxyl group of tapentadol, and the hydrolysis rate and speed can be controlled by optimizing the steric hindrance of ester substituent. The selected prodrugs are evaluated on cell level, organization level and the whole animal level, and the qualitative and quantitative relationships between substituent and presystemic stability are established to optimize the design and synthesis of tapentadol carbamate ester prodrug and to screen the optimal tapentadol analogues. The results of the research provide a universal solution to the oral bioavailability enhancement of drugs with phenolic hydroxyl groups and strong first-pass effect.