Discovery of novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

Abstract

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.

• Authors: Xiangdong Su, Nigel Vicker, Melanie Trusselle, Heather Halem, Michael D Culler, Barry V L Potter
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 301 Issue 1-2 Pg. 169-73 (Mar 25 2009) ISSN: 0303-7207 [Print] Ireland
• PMID: 18775471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• NADP
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• HSD11B1 protein, human
• Cortisone
• Hydrocortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• Cell Line
• Cortisone (chemistry, metabolism)
• Drug Discovery
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Hydrocortisone (chemistry, metabolism)
• Inhibitory Concentration 50
• Models, Molecular
• NADP (metabolism)