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11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11beta-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 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11beta-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11beta-HSD1 with IC(50) 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 11beta-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.

Original publication

DOI

10.1002/cmdc.201000081

Type

Journal article

Journal

ChemMedChem

Publication Date

05/07/2010

Volume

5

Pages

1026 - 1044

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Adamantane, Amines, Benzamides, Cell Line, Computer Simulation, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Drug Discovery, Enzyme Inhibitors, Humans, Microsomes, Liver, Structure-Activity Relationship