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Specific inhibitors of 11beta-HSD1

The crucial point in glucocorticoid related diseases, including type 2 diabetes, metabolic syndrome, obesity, hyperglycaemia, arteriosclerosis, dementia, depression and osteoporosis is the ratio of cortisone/cortisol, too much cortisol results in described diseases.

11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) plays an important role in converting cortisone to cortisol, while 11beta-hydroxysteroid dehydrogenase type 2 (11b-HSD2) only acts as a deydrogenase by inactivating cortisol to cortisone. Due to their non-specificity compounds like 18beta-Glycyrrhetinic acid cause adverse effects, among other things hypertension. Therefore, a selective inhibitor of 11b-HSD1 has considerable potential as a drug directed against glucocorticoid related metabolic disorders. The invention results in new compounds with an oleanan or ursan scaffold which specific inhibit 11b-HSD1 and not 11b-HSD2. The structural determinants for specific inhibition are figured out and new approaches to synthesize specific 11b-HSD1 inhibitors with oleanan or ursan scaffold are shown. Selective 11b-HSD1 inhibitors with an oleanan or ursan scaffold should have the advantage of low toxicity, the possibility of modification of the scaffold to influence pharmacokinetic and –dynamic properties, as well as sufficient sources in nature.

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Dr. Alexandra Baumgartner | TechnologieAllianz e.V.
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