Selective inhibition of 11β-hydroxysteroid dehydrogenase 1 by 18α-glycyrrhetinic acid but not 18β-glycyrrhetinic acid

Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active Ilp-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11 beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18 beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11 beta-HSD1 and 11 beta-HSD2. Here, we compare the biological activity of 18 beta-GA and its diastereomer 18 alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18 alpha-GA selectively inhibits 11 beta-HSD1 but not 11 beta-HSD2. This is in contrast to 18 beta-GA, which preferentially inhibits 11 beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11 beta-HSD1, we provide an explanation for the differences in the activities of 18 alpha-GA and 18 beta-GA. This model will be used to design novel selective derivatives of GA. (C) 2009 Elsevier Ltd. All rights reserved.