Discovery and structure–activity relationships of pentanedioic acid diamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type I

Benzylamides of pentanedioic acid were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC50s on the 11β-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11β-HSD1 (IC50 < 0.1 μM) in a cellular model (3T3L1 adipocytes).

A hit identified from high throughput screening led after Hit-to-Lead-optimisation to a single digit nanomolar inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) suitable for in vivo administration.Figure optionsDownload as PowerPoint slide