On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11尾-hydroxysteroid dehydrogenase type 1 (11尾-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11尾-HSD-1 and dose-dependent in vivo inhibition of 11尾-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.