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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




Journal article



Publication Date





1439 - 1451


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