Discovery of adamantyl ethanone derivatives as potent 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors.

Abstract

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.

• Authors: Xiangdong Su, Fabienne Pradaux-Caggiano, Mark P Thomas, Michelle W Y Szeto, Heather A Halem, Michael D Culler, Nigel Vicker, Barry V L Potter
• Journal: ChemMedChem (ChemMedChem) Vol. 5 Issue 7 Pg. 1026-44 (Jul 05 2010) ISSN: 1860-7187 [Electronic] Germany
• PMID: 20486152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(2-adamantan-1-yl-2-oxoethoxymethyl)-N,N-dimethylbenzamide
• Amines
• Benzamides
• Cytochrome P-450 Enzyme Inhibitors
• Enzyme Inhibitors
• benzamide
• Cytochrome P-450 Enzyme System
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Adamantane

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, metabolism)
• Adamantane (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Amines (chemical synthesis, chemistry, pharmacology)
• Benzamides (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Computer Simulation
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Drug Discovery
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Microsomes, Liver (metabolism)
• Structure-Activity Relationship