Liguzinediol芳酸单酯前药的合成、理化性质及血浆酶解评价

发布时间：2018-08-27 19:30

【摘要】：目的:设计合成系列liguzinediol的芳酸单酯前药,通过理化性质和人体血浆酶解特性研究,筛选出适合liguzinediol口服给药的候选前药。方法:以吡啶催化的酰氯与醇的酯合成法及DMAP催化的酸与醇的DCC缩合法,共合成6个liguzinediol的芳酸单酯类前药,用红外、质谱、核磁共振氢谱和碳谱进行结构确认。采用高效液相色谱法测定化合物的容量因子、溶解度、p H 7.4的化学稳定性以及体外80%人血浆中酯酶水解的释放特性。结果:liguzinediol的糠酸单酯、3-氯苯甲酸单酯与苯甲酸单酯血浆酶解速率过快;4-二甲氨基苯甲酸单酯化学稳定性较差;4-甲氧基苯甲酸单酯化学稳定性高,酶解释放速率适中。结论:liguzinediol的4-甲氧基苯甲酸单酯化学稳定性较高,体外80%人血浆酶解liguzinediol释放速率合适,可以作为liguzinediol口服给药形式的候选药物前体。
[Abstract]:Aim: to design and synthesize a series of aryl acid monoester prodrugs of liguzinediol, and to select the candidate prodrugs suitable for oral administration of liguzinediol by studying their physicochemical properties and human plasma enzymatic properties. Methods: six prodrugs of aromatic acid monoesters of liguzinediol were synthesized by the synthesis of acyl chloride and alcohols catalyzed by pyridine and DCC condensation of acids and alcohols catalyzed by DMAP. The structures were confirmed by IR, MS, NMR and C spectra. The volume factor, the chemical stability of solubility pH 7.4 and the release characteristics of esterase hydrolysis in 80% human plasma in vitro were determined by high performance liquid chromatography (HPLC). Results the rate of plasma enzymatic hydrolysis of monoester 3-chlorobenzoate and monoester of benzoic acid of 1% liguzinediol was too fast and the chemical stability of monoester of 4-dimethylaminobenzoate was poor, and the rate of release of monoester of 4-methoxy benzoate was moderate. Conclusion the chemical stability of the 4-methoxybenzoate monoester of 1: liguzinediol is high, and the release rate of liguzinediol is suitable for 80% human plasma in vitro. It can be used as a drug precursor for oral administration of liguzinediol.
【作者单位】：南京中医药大学药学院;
【基金】：国家自然科学基金(81072542) 高等学校博士学科点专项科研基金(20123237110010) 江苏省自然科学基金(BK2011077,BK20131262) 江苏高校优势学科建设工程资助项目
【分类号】：R914

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