Discovery of Adamantyl Ethanone Derivatives as Potent 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors

11 beta-Hydroxysteroid dehydrogenases (11 beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticold hormones. The modulation of 11 beta-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 11 beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11 beta-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11 beta-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 11 beta-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.