title: Discovery and structure-activity relationships of pentanedioic acid diamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type I.
abstract: Benzylamides of pentanedioic acid were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11beta-HSD1 (IC(50)<0.1microM) in a cellular model (3T3L1 adipocytes).
authors.affiliation: Merck-Serono, Chilly-Mazarin, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Roche
authors.forename: Denis
authors.initials: D
authors.lastname: Carniato
authors.forename: Caroline
authors.initials: C
authors.lastname: Leriche
authors.forename: Franck
authors.initials: F
authors.lastname: Lepifre
authors.forename: Serge
authors.initials: S
authors.lastname: Christmann-Franck
authors.forename: Ulrich
authors.initials: U
authors.lastname: Graedler
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; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D041721:3T3-L1 Cells; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2