Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin

A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiatio...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2013-07, Vol.49 (4), p.624-628
Main Authors: Huttunen, Kristiina M., Leppänen, Jukka, Laine, Krista, Vepsäläinen, Jouko, Rautio, Jarkko
Format: Article
Language:English
Subjects:
Animals
Caco-2 Cells
Chemistry, Pharmaceutical - methods
Cysteine - metabolism
Glutathione - metabolism
Humans
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - metabolism
Lipophilic
Metformin
Metformin - chemistry
Metformin - metabolism
Microwave-assisted synthesis
Microwaves
Permeability
Prodrug
Prodrugs - chemical synthesis
Prodrugs - metabolism
Rats
Sulfamerazine - chemical synthesis
Sulfamerazine - metabolism
Sulfenamide
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Summary:A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin.
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2013.05.023