Piperazine Sulfonamides as Potent, Selective, and Orally Available 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors with Efficacy in the Rat Cortisone-Induced Hyperinsulinemia Model

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11β-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure−activity relationship, and in vivo evaluation of piperazine sulfonamides as 11β-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11β-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.