title: Discovery of novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
abstract: 11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones, which play essential roles in various vital physiological processes. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Therefore, inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. Here we report the discovery of a series of novel adamantyl carboxamides as selective inhibitors of human 11beta-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Compounds 9 and 14 show inhibitory activity against 11beta-HSD1 with IC(50) values in 100nM range. Docking studies with the potent compound 8 into the crystal structure of human 11beta-HSD1 (1XU9) reveals how the molecule may interact with the enzyme and cofactor.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath BA2 7AY, UK.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Su
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Melanie
authors.initials: M
authors.lastname: Trusselle
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; D002460:Cell Line; D003348:Cortisone / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009249:NADP / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009249:NADP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone