title: Adamantyl ethanone pyridyl derivatives: potent and selective inhibitors of human 11β-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. 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.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA27AY, UK.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Su
authors.forename: Fabienne
authors.initials: F
authors.lastname: Pradaux-Caggiano
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Heather
authors.initials: H
authors.lastname: Halem
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane