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Simultaneous measurement of metabolic stability and metabolite identification of 7‐methoxymethylthiazolo[3,2‐a]pyrimidin‐5‐one derivatives in human liver microsomes using liquid chromatography/ion‐trap mass spectrometry
Author(s) -
Kantharaj E.,
Ehmer Peter B.,
Tuytelaars An,
Vlaslaer Anne Van,
Mackie Claire,
Gilissen Ron A. H. J.
Publication year - 2005
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.1891
Subject(s) - chemistry , metabolite , mass spectrometry , chromatography , microsome , epoxide , tandem mass spectrometry , metabolic pathway , ion trap , liquid chromatography–mass spectrometry , double bond , metabolism , organic chemistry , biochemistry , enzyme , catalysis
Abstract A liquid chromatography/mass spectrometry (LC/MS) method using an atmospheric pressure chemical ionisation source was used to measure the metabolic stability and metabolite identification of 7‐methoxymethylthiazolo[3,2‐a]pyrimidin‐5‐one derivative (1) in human liver microsomes. After 15 min incubation with human liver microsomes, compound 1 exhibited metabolic turnover of 44%. Data‐dependent tandem mass spectrometry (MS/MS) scanning was used to generate product ion spectra from the protonated ions of the compound and its metabolites. An unusual metabolite at m/z 407 corresponding to the [M–24+H] + ion was identified for compound 1. Interestingly, the formation of the [M–24+H] + ion was not observed in the analogues wherein the fused thieno double bond was substituted (2) and the thieno group replaced by a fused benzo derivative (3). Compounds 2 and 3 exhibited metabolic turnovers of 24 and 30%, yielding oxidative metabolites corresponding to [M+16] and [M+32] + , respectively. Based on these facts the mechanism for [M–24] + formation in compound 1 through an initial epoxide formation on the double bond of the fused thieno ring followed by hydrolytic ring opening and deacylation is envisaged. Copyright © 2005 John Wiley & Sons, Ltd.