Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1
journal contributionposted on 20.10.2005 by Gary M. Coppola, Paivi J. Kukkola, James L. Stanton, Alan D. Neubert, Nicholas Marcopulos, Natalie A. Bilci, Hua Wang, Hollis C. Tomaselli, Jenny Tan, Thomas D. Aicher, Douglas C. Knorr, Arco Y. Jeng, Beatriz Dardik, Ricardo E. Chatelain
Any type of content formally published in an academic journal, usually following a peer-review process.
High-throughput screening identified 5 as a weak inhibitor of 11β-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 11β-HSD2. Analogues which showed >50% inhibition of 11β-HSD1 at 1 μM 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.