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 optimization process of the series, knowledge of absorption, distribution, metabolism, excretion, and toxicity parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds [7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73) and 7-chloro-3-(3-pentylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide (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 analyzed by both mass spectrometry (MS) and NMR to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of nontreated rats and human microsomes to compare the metabolic profiles. In the present study, the combined use of an exact mass liquid chromatography (LC)/tandem MS platform and an LC/solid-phase extraction/NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCO drugs. These results greatly help the optimization of the lead compounds.
Footnotes
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This work was supported by grants from the National Fund for Scientific Research (Belgium).
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P.d.T. and M.F. are Senior Research Associates for the National Fund for Scientific Research (Belgium). P.L. is Research Director for the National Fund for Scientific Research (Belgium).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028928.
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- KATP channel
- ATP-sensitive potassium channel
- PCO
- potassium channel opener
- BPDZ 73
- 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
- BPDZ 157
- 7-chloro-3-(3-pentylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
- PB
- phenobarbital
- P450
- cytochrome P450
- LC
- liquid chromatography
- SPE
- solid-phase extraction
- MS/MS
- tandem mass spectrometry
- ACN
- acetonitrile
- COSY
- correlation spectroscopy
- BPDZ 44
- 3-(1′,2′-dimethylpropyl)amino-4H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide
- BPDZ 154
- 6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
- BPDZ 414
- 6,7-difluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
- BPDZ 256
- 6-chloro-3-cyclobutylamino-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide.
- Received June 10, 2009.
- Accepted October 27, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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