Adamantyl ethanone pyridyl derivatives: potent and selective inhibitors of human 11?-hydroxysteroid dehydrogenase type?1.

ABSTRACT: Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type?2 diabetes and obesity. 11?-Hydroxysteroid dehydrogenase type?1 (11?-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11?-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11?-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11?-HSD1 and are selective for this isoform, with no activity against 11?-HSD2 and 17?-HSD1. Structure-activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC?? values around 34-48?nM against human 11?-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.

SUBMITTER: Su X 

PROVIDER: S-EPMC3179844 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature