title: Novel non-steroidal inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
abstract: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regulates glucocorticoid action at the pre-receptor stage by converting cortisone to cortisol. 11beta-HSD1 is selectively expressed in many tissues including the liver and adipose tissue where metabolic events are important. Metabolic syndrome relates to a number of metabolic abnormalities and currently has a prevalence of >20% in adult Americans. 11beta-HSD1 inhibitors are being investigated by many major pharmaceutical companies for type 2 diabetes and other abnormalities associated with metabolic syndrome. In this area of intense interest a number of structural types of 11beta-HSD1 inhibitor have been identified. It is important to have an array of structural types as the physicochemical properties of the compounds will determine tissue distribution, HPA effects, and ultimately clinical utility. Here we report the discovery and synthesis of three structurally different series of novel 11beta-HSD1 inhibitors that inhibit human 11beta-HSD1 in the low micromolar range. Docking studies with 1-3 into the crystal structure of human 11beta-HSD1 reveal how the molecules may interact with the enzyme and cofactor and give further scope for structure based drug design in the optimisation of these series.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath BA2 7AY, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Su
authors.forename: Dharshini
authors.initials: D
authors.lastname: Ganeshapillai
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D001549:Benzamides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005449:Fluorenes; D013449:Sulfonamides; D013844:Thiazoles; D013876:Thiophenes; C522170:3,5-dichloro-N-(2-methylbenzothiazol-5-yl)benzamide; C522171:3-chloro-2-methyl-N-(9-oxo-9H-fluoren-3-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C522172:4-propyl-N-(2-thiophen-2-ylethyl)benzenesulfonamide; C522169:BVT.14225; C468386:HSD11B1 protein, human