Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro.

Acta Pharmacol Sin. 2009 Aug 24; Zhang X, Zhou Y, Shen Y, Du LL, Chen JH, Leng Y, Shen JHAbstractAim:To design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework.Methods:Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1.Results:Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC(50) values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results.Conclusion:This study provides two promising new templates for 11beta-HSD1 inhibitors.Acta Pharmacologica Sinica advance online publication, 24 August 2009; doi: 10.1038/aps.2009.118.