Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11ß-hydroxysteroid dehydrogenase 2 inhibitors.

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 and type 2. Whereas inhibition of 11ß-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11ß-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11ß-HSD2. The most potent and selective compound is active against human 11ß-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11ß-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11ß-HSD1 and 11ß-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11ß-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.

Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11ß-hydroxysteroid dehydrogenase 2 inhibitors.

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 and type 2. Whereas inhibition of 11ß-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11ß-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11ß-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11ß-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11ß-HSD1 and 11ß-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11ß-HSD2. The most potent and selective compound is active against human 11ß-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11ß-HSD1.

Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases.

The effect of glycyrrhetinic acid (GA) and GA-derivatives towards 11beta-hydroxysteroid dehydrogenase (11beta-HSD) was investigated. Novel compounds with modifications at positions C-3, C-11 and C-29 of the GA skeleton were prepared. Single crystal X-ray diffraction data of selected substances are reported and discussed.

(+)-Methyl 3ß-acet-oxy-13-carb-oxy-19-hy-droxy-11-oxo-C-norolean-18-en-30-oate γ-lactone.

The title compound, C(33)H(46)O(7), is an unusual oxydation product of the therapeutic agent glycyrrhetinic acid that has, in comparison to the latter, a distinctly altered triterpene structure with one five- and four six-membered carbocycles complemented by a γ-lactone ring with a spiro-junction and a ring double bond. The junction between the five-membered ring C, a cyclo-penta-none ring, and the six-membered ring D, previously in question, was found to be cis, confirming earlier structure assignments based solely on chemical transformations. In the solid state, the compound exhibits five intra- and four inter-molecular C-H⋯O inter-actions with H⋯O distances less than or equal to 2.70 Šand C-H⋯O greater than 100°.