911057-89-1Relevant articles and documents
Discovery of adamantyl ethanone derivatives as potent 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors
Su, Xiangdong,Pradaux-Caggiano, Fabienne,Thomas, Mark P.,Szeto, Michelle W. Y.,Halem, Heather A.,Culler, Michael D.,Vicker, Nigel,Potter, Barry V. L.
experimental part, p. 1026 - 1044 (2011/02/21)
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.
