Inhibition of human and rat 11β-hydroxysteroid dehydrogenase type 1 by 18β-glycyrrhetinic acid derivatives

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays an important role in regulating the cortisol availability to bind to corticosteroid receptors within specific tissue. Recent advances in understanding the molecular mechanisms of metabolic syndrome indicate that elevation of cortisol levels within specific tissues through the action of 11 beta-HSD1 could contribute to the pathogenesis of this disease. Therefore, selective inhibitors of 11 beta-HSD1 have been investigated as potential treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here we report the discovery and synthesis of some 18 beta-glycyrrhetinic acid (18 beta-GA) derivatives (2-5) and their inhibitory activities against rat hepatic 11 beta-HSD1 and rat renal 11 beta-HSD2. Once the selectivity over the rat type 2 enzyme was established, these compounds' ability to inhibit human 11 beta-HSD1 was also evaluated using both radioimmunoassay (RIA) and homogeneous time resolved fluorescence (HTRF) methods. The 11-modified 18 beta-GA derivatives 2 and 3 with apparent selectivity for rat 11 beta-HSD1 showed a high percentage inhibition for human microsomal 11 beta-HSD1 at 10 mu M and exhibited IC50 values of 400 and 1100 nM, respectively. The side chain modified 18 beta-GA derivatives 4 and 5, although showing selectivity for rat 11 beta P-HSD1 inhibited human microsomal 11 beta-HSD1 with IC50 values in the low micromolar range. (c) 2007 Elsevier Ltd. All rights reserved.