title: Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
abstract: High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.
authors.affiliation: Department of Metabolic and Cardiovascular Diseases, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. gary.coppola@novartis.com
authors.forename: Gary M
authors.initials: GM
authors.lastname: Coppola
authors.forename: Paivi J
authors.initials: PJ
authors.lastname: Kukkola
authors.forename: James L
authors.initials: JL
authors.lastname: Stanton
authors.forename: Alan D
authors.initials: AD
authors.lastname: Neubert
authors.forename: Nicholas
authors.initials: N
authors.lastname: Marcopulos
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bilci
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Hollis C
authors.initials: HC
authors.lastname: Tomaselli
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Knorr
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Beatriz
authors.initials: B
authors.lastname: Dardik
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Chatelain
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000315:Adrenalectomy; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D006873:Hydroquinones; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone