11β-Hydroxysteroid dehydrogenases (11β-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11β-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11β-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11β-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11β-HSD1 with IC50 values in the 50–70 nM range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in vivo studies. Comparison of the publicly available X-ray crystal structures of human 11β-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.
- hydroxysteroid dehydrogenase
- metabolic syndrome
- adamantyl ethanones
- 11 beta-HSD1
Su, X., Pradaux-Caggiano, F., Thomas, M. P., Szeto, M. W. Y., Halem, H. A., Culler, M. D., Vicker, N., & Potter, B. V. L. (2010). Discovery of adamantyl ethanone derivatives as potent 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD1) inhibitors. ChemMedChem, 5(7), 1026-1044. https://doi.org/10.1002/cmdc.201000081