Abstract
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.
- analytical chemistry
- cytochrome P450
- drug development
- mass spectrometry
- metabolite identification
- structure elucidation
Footnotes
- Received June 22, 2009.
- Accepted October 27, 2009.
- The American Society for Pharmacology and Experimental Therapeutics