Liguzinediol乙酰氨基酸双酯前药的设计、合成及生物活性评价  

Design,synthesis and biological evalution of liguzinediol acetyl amino acid dual ester prodrugs as promissing inotropic agents

作　　者：沈敏哲 李智[1] 李伟[1] 文红梅[1] 刘健[1] 朱浩浩[1] 钱程博 蔡建国[1] 

机构地区：[1]南京中医药大学药学院,江苏省中药功效物质重点实验室,南京210023

出　　处：《中国新药杂志》2017年第5期548-554,共7页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81573304);高等学校博士学科点专项科研基金资助项目(20123237110010);江苏省高校优势学科建设工程资助项目

摘　　要：目的:设计、合成liguzinediol的乙酰氨基酸酯前药,结合化学稳定性、理化性质以及体外、体内药动学研究,考察其生物活性,筛选出适合的候选前药。方法:采用4-二甲氨基吡啶(DMAP)催化、N,N'-二环己基碳二亚胺(DCC)缩合liguzinediol乙酰氨基酸酯前药,化合物结构经LC-MS,1H-NMR和13C-NMR确证。采用高效液相色谱法(HPLC)测定化合物的化学稳定性、容量因子、脂水分配系数以及溶解度,并进行了体外生物转化稳定性和体内药动学研究。结果:liguzinediol的乙酰缬氨酸、亮氨酸与异亮氨酸双酯前药酶解速率过低;乙酰苯丙氨酸双酯的水溶性较差;乙酰甘氨酸双酯化学稳定性高,酶解释放速率适中。结论:liguzinediol的乙酰甘氨酸酯化学稳定性较高,体外80%人体血浆以及肝微粒体酶解liguzinediol释放速率合适,可作为liguzinediol的候选药物。Objective： Design and synthesis acetyl amino acid dual ester prodrugs of liguzinediol,investigate the chemical stability and physicochemical properties,and study the pharmacokinetic both in vitro and in vivo to find a suitable agent. Methods： Liguzinediol was coupled with each acetyl amino acid via the DMAP-catalyzed and DCC-condensated. The structure was characterized by LC-MS,1H-NMR and13C-NMR. HPLC method was used to test the chemical stability, capacity factor, solubility, lipophilicity, and in vitro bioconversion and in vivo pharmacokinetic of various parameters of all prodrugs. Results： N-acetyl-L-valine,N-acetyl-L-leucine and N-acetylL-isoleucine dual ester released liguzinediol too slow to be a controlled prodrug. The solubility of N-acetyl-Lphenylalanine dual ester was poor. Among the eight prodrugs,N-acetylglycine dual ester not only released liguzinediol moderately but also showed highly chemical stability. Conclusion： The N-acetylglycine dual ester may be a promising prodrug with the advantages of highly chemical stability and moderate releasing rate.

关 键 词：LIGUZINEDIOL 乙酰氨基酸 双酯前药 物理化学性质 药动学 

分 类 号：R969.1[医药卫生—药理学]