Discovery of adamantyl heterocyclic ketones as potent 11β-hydroxysteroid dehydrogenase type 1 inhibitors.

Abstract

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

• Authors: Xiangdong Su, Nigel Vicker, Mark P Thomas, Fabienne Pradaux-Caggiano, Heather Halem, Michael D Culler, Barry V L Potter
• Journal: ChemMedChem (ChemMedChem) Vol. 6 Issue 8 Pg. 1439-51 (Aug 01 2011) ISSN: 1860-7187 [Electronic] Germany
• PMID: 21608132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Cytochrome P-450 Enzyme Inhibitors
• Enzyme Inhibitors
• Heterocyclic Compounds
• Ketones
• Cytochrome P-450 Enzyme System
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, metabolism)
• Animals
• Binding Sites
• Computer Simulation
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Heterocyclic Compounds (chemistry)
• Humans
• Ketones (chemical synthesis, chemistry, pharmacology)
• Mice
• Microsomes, Liver (metabolism)
• Structure-Activity Relationship