Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors

The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported. A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure–activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC50=1.8 and 1.4nM, respectively).