Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1002/cmdc.201100144

Type

Journal article

Journal

ChemMedChem

Publication Date

01/08/2011

Volume

6

Pages

1439 - 1451

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Animals, Binding Sites, Computer Simulation, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Drug Evaluation, Preclinical, Enzyme Inhibitors, Heterocyclic Compounds, Humans, Ketones, Mice, Microsomes, Liver, Structure-Activity Relationship