Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1
2005-10-20T00:00:00Z (GMT) by
High-throughput screening identified <b>5</b> 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; <b>9m</b>, <b>25</b> and <b>49</b>.