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11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones, which play essential roles in various vital physiological processes. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Therefore, inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. Here we report the discovery of a series of novel adamantyl carboxamides as selective inhibitors of human 11beta-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Compounds 9 and 14 show inhibitory activity against 11beta-HSD1 with IC(50) values in 100nM range. Docking studies with the potent compound 8 into the crystal structure of human 11beta-HSD1 (1XU9) reveals how the molecule may interact with the enzyme and cofactor.

Original publication

DOI

10.1016/j.mce.2008.08.006

Type

Journal article

Journal

Mol Cell Endocrinol

Publication Date

25/03/2009

Volume

301

Pages

169 - 173

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Cell Line, Cortisone, Drug Discovery, Enzyme Inhibitors, Humans, Hydrocortisone, Inhibitory Concentration 50, Models, Molecular, NADP