Discovery and structure-guided drug design of inhibitors of 11β-hydroxysteroid-dehydrogenase type I based on a spiro-carboxamide scaffold

Spiro-carboxamides were identified as inhibitors of 11 beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC50 inhibitor (0.5 nM) on human 11 beta-HSD1 with a high binding efficiency index (BEI of 32.7) which was selective against human 11 beta-HSD2 (selectivity ratio > 200000). (C) 2009 Published by Elsevier Ltd.