抗HIV先导物DAAN-4048在大鼠肝微粒体的代谢产物  

Metabolite profiling of anti-HIV lead compound DAAN-4048 in rat liver microsomes

作　　者：王瑞[1,2] 魏霞[2] 陈佳[2] 秦炳杰[2] 谢剑炜[2] 李桦[2] 谢蓝[2] 

机构地区：[1]北京军区总医院药剂科,北京100700 [2]军事医学科学院毒物药物研究所,北京100850

出　　处：《国际药学研究杂志》2013年第4期491-496,共6页Journal of International Pharmaceutical Research

基　　金：国家自然科学基金重点项目(30930106);国家"重大新药创制"科技重大专项资助项目(2008ZXJ09006-001)

摘　　要：目的应用超高效液相色谱-四极杆飞行时间质谱联用技术(UPLC-QTOF-MS/MS)并辅以代谢数据采集和处理软件,快速筛查和鉴定了新型非核苷类逆转录酶抑制剂的先导物二芳烃取代苯胺类化合物(DAAN)-4048在大鼠肝微粒体的代谢产物,并分析结构中的代谢软点。方法应用质量亏损过滤技术在UPLC-QTOF-MS/MS上比较分析0 h与2 h孵育样品的数据,在大鼠肝微粒体孵育液中筛查得到了DAAN-4048的10个代谢产物。应用仪器的碰撞能量梯度功能(MSE)对部分产物进行MS2分析,获得代谢产物的碎片,推断碎裂途径及产物结构。结果结果表明,先导物在大鼠肝微粒体中发生广泛的代谢,Ⅰ相代谢反应以氧化(羟基化)为主,Ⅱ相代谢主要以谷胱甘肽结合反应为主。结论本文通过分析新型抗HIV先导物DAAN-4048的结构和代谢转化,发现易于发生代谢的位点和结构特征,为该类先导物结构优化和后续的临床前评价提供了科学指导。Objective To perform the metabolite profiling of diarylaniline（DAAN）-4048,the lead compound from new classes of non-nucleoside reverse transcriptase inhibitors（NNRTI）,by using an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry（LC-QTOF-MS / MS）,with the assistance of a metabolite data processing software.Methods By applying the mass defect filter（MDF） technique,the data acquired from the 0 h-incubate and the 2 h-incubate were compared and analyzed with the software.A total of 10 metabolites were found for DAAN-4048 in the 2 h-incubate.The MS2 spectra for some metabolites were obtained using the MSE technique to get fragment ions for structural elucidation.Results The results indicated the major metabolic pathways.The compound could undergo extensive metabolism in rat liver microsomes.The major phase Ⅰ reactions were oxidation / hydroxylation.The major phase Ⅱ reactions were S-glutathione conjugation.Conclusion The structure-metabolic pathway relationship was analyzed to reveal metabolic soft spots and the structure characterizations of the compound.This may provide scientific directions for lead structural optimization,as well as for further preclinical evaluation of the new chemical entities.

关 键 词：非核苷类逆转录酶抑制剂 二芳烃取代苯胺类化合物 大鼠肝微粒体 代谢产物 超高效液相色谱-四极杆飞行时间质谱 

分 类 号：R96[医药卫生—药理学]