[Back]

D. Classen-Houben, D. Schuster, T. Da Cunha, A. Odermatt, G. Wolber, U. Jordis, B. Küenburg:
"Selective inhibition of 11beta -hydroxysteroid dehydrogenase 1 by 18alpha -glycyrrhetinic acid but not 18beta -glycyrrhetinic acid";
Journal of Steroid Biochemistry and Molecular Biology, 113 (2009), 248 - 252.

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

glycyrrhetic acids stereochem oxidn stereochem oxidn glycyrrhetic acids