1185752-80-0Relevant articles and documents
Adamantyl ethanone pyridyl derivatives: Potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
Su, Xiangdong,Pradaux-Caggiano, Fabienne,Vicker, Nigel,Thomas, Mark P.,Halem, Heather,Culler, Michael D.,Potter, Barry V.L.
, p. 1616 - 1629 (2012/01/04)
Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type2 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 34-48nM against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.
