Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers
[en] SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity and hyperinsulinemia. Taking into account these promising therapeutic benefits, different series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide were developed. In view of the lead optimisation process of the series, knowledge of ADMET parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds (BPDZ 73 and BPDZ 157) were incubated in the presence of phenobarbital-induced rat liver microsomes to produce expected mammal in vivo phase I metabolites. The resulting major metabolites were then analysed by both MS and NMR in order to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of non-treated rats and human microsomes in order to compare the metabolic profiles. In the present study, the combined use of an exact mass LC-MS/MS platform and a LC-SPE-NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCOs drugs. These results greatly help the optimization of the lead compounds.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Gillotin, F.
Chiap, Patrice ; Centre Hospitalier Universitaire de Liège - CHU > Pharmacologie clinique
Frederich, Michel ; Université de Liège - ULiège > Département de pharmacie > Pharmacognosie
Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Lebrun, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers
Publication date :
2010
Journal title :
Drug Metabolism and Disposition: the Biological Fate of Chemicals
ISSN :
0090-9556
eISSN :
1521-009X
Publisher :
Williams and Wilkins, Baltimore, United States - Maryland
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