title: [Metabolite profiling of two anti-HIV lead compounds in rat liver microsomes].
abstract: The metabolite profiling of DAPA-7012 and DAAN-4442, the lead compounds from two new kinds of non-nucleoside reverse transcriptase inhibitors (NNRTIs), was performed using an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), with the assistance of a metabolite data processing software. By utilizing the mass defect filter (MDF) technique, the data acquired from the 0 h-incubation and the 2 h-incubation were compared and analyzed with the MetaboLynx software. After incubation, 14 metabolites of DAPA-7012 and 14 metabolites of DAAN-4442 were found in rat liver microsome. The MS2 spectra for some metabolites were obtained using the MS(E) technique to get fragment ions for structural elucidation. The results indicated that both compounds could undergo extensive metabolism in rat liver microsomes. The major phase I reaction was oxidation/hydroxylation. The major phase II reaction was S-glutathione conjugation. The metabolic pathways were similar between the two lead compounds, though they have different backbone structures. Besides, the 4-NO2 of ring B in DAAN-4442 was susceptible to reduction, the benzyl of ring C in DAPA-7012 was tend to be oxidized. The common metabolic soft spots were primary amine of ring B and two methyl groups of ring C. Early SAR results showed that the primary amine and methyl were necessary substituent groups. The stability of these active groups needs to be improved and optimized. The approach of combining metabolites information and structure-activity analysis can provide a reference for further structural optimization.
authors: Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors: Rui
authors: R
authors: Wang
authors: Jia
authors: J
authors: Chen
authors: Bing-Jie
authors: BJ
authors: Qin
authors: Jian-Wei
authors: JW
authors: Xie
authors: Hua
authors: H
authors: Li
authors: Lan
authors: L
authors: Xie
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000814:Aniline Compounds; D019380:Anti-HIV Agents; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors