title: Discovery and structure-guided drug design of inhibitors of 11beta-hydroxysteroid-dehydrogenase type I based on a spiro-carboxamide scaffold.
abstract: Spiro-carboxamides were identified as inhibitors of 11beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC(50) inhibitor (0.5nM) on human 11beta-HSD1 with a high binding efficiency index (BEI of 32.7) which was selective against human 11beta-HSD2 (selectivity ratio>200000).
authors.affiliation: Merck-Serono, 4 Avenue du Président Mitterrand, 91380 Chilly-Mazarin, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Lepifre
authors.forename: Serge
authors.initials: S
authors.lastname: Christmann-Franck
authors.forename: Didier
authors.initials: D
authors.lastname: Roche
authors.forename: Caroline
authors.initials: C
authors.lastname: Leriche
authors.forename: Denis
authors.initials: D
authors.lastname: Carniato
authors.forename: Christine
authors.initials: C
authors.lastname: Charon
authors.forename: Sophie
authors.initials: S
authors.lastname: Bozec
authors.forename: Liliane
authors.initials: L
authors.lastname: Doare
authors.forename: Fabien
authors.initials: F
authors.lastname: Schmidlin
authors.forename: Marc
authors.initials: M
authors.lastname: Lecomte
authors.forename: Eric
authors.initials: E
authors.lastname: Valeur
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1