Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1

• Published in: Journal of medicinal chemistry Vol. 48; no. 21; pp. 6696 - 6712
• Main Authors: Coppola, Gary M, Kukkola, Paivi J, Stanton, James L, Neubert, Alan D, Marcopulos, Nicholas, Bilci, Natalie A, Wang, Hua, Tomaselli, Hollis C, Tan, Jenny, Aicher, Thomas D, Knorr, Douglas C, Jeng, Arco Y, Dardik, Beatriz, Chatelain, Ricardo E
• Format: Journal Article
• Language: English
• Published: United States 20-10-2005
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; Adrenalectomy; Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Cells, Cultured; Corticosterone - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Hydroquinones - chemical synthesis; Hydroquinones - chemistry; Hydroquinones - pharmacology; Liver - drug effects; Liver - metabolism; Male; Mice; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623

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.