Discovery And Structure-Activity Relationships Of Pentanedioic Acid Diamides As Potent Inhibitors Of 11 Beta-Hydroxysteroid Dehydrogenase Type I

Benzylamides of pentanedioic acid were identified as inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11 beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11 beta-hydroxysteroid dehydrogenase type 2 ( selectivity ratio > 1000) and displayed good inhibition of 11 beta-HSD1 (IC50 < 0.1 mu M) in a cellular model (3T3L1 adipocytes). (C) 2009 Elsevier Ltd. All rights reserved.