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 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11 beta-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 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11b-HSD1 and are selective for this isoform, with no activity against 11 beta-HSD2 and 17 beta-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(50) values around 34-48 nm against human 11 beta-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.
- metabolic syndrome
- adamantyl ethanones
- hydroxysteroid dehydrogenases
- 11 beta-HSD1
Su, X., Pradaux-Caggiano, F., Vicker, N., Thomas, M. P., Halem, H., Culler, M. D., & Potter, B. V. L. (2011). Adamantyl ethanone pyridyl derivatives: potent and selective inhibitors of human 11 beta-hydroxysteroid dehydrogenase type 1. ChemMedChem, 6(9), 1616-1629. https://doi.org/10.1002/cmdc.201100182