AIM: 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 IC50 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.
AIM: 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 mouse11beta-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 IC50 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.
Authors: Janice M Paterson; Nicholas M Morton; Catherine Fievet; Christopher J Kenyon; Megan C Holmes; Bart Staels; Jonathan R Seckl; John J Mullins Journal: Proc Natl Acad Sci U S A Date: 2004-04-26 Impact factor: 11.205
Authors: Jeremy W Tomlinson; Elizabeth A Walker; Iwona J Bujalska; Nicole Draper; Gareth G Lavery; Mark S Cooper; Martin Hewison; Paul M Stewart Journal: Endocr Rev Date: 2004-10 Impact factor: 19.871