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

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.