Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin

• 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
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2013.05.023

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.