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Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type 2 diabetes and obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11β-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 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective for this isoform, with no activity against 11β-HSD2 and 17β-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 IC₅₀ values around 34-48 nM against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.

Original publication

DOI

10.1002/cmdc.201100182

Type

Journal article

Journal

ChemMedChem

Publication Date

05/09/2011

Volume

6

Pages

1616 - 1629

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Adamantane, Animals, Cell Line, Cytochrome P-450 Enzyme System, Enzyme Inhibitors, HEK293 Cells, Humans, Hydroxysteroid Dehydrogenases, Kidney, Metabolic Diseases, Mice, Pyridines, Structure-Activity Relationship