Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of Potent and Selective Inhibitors of the 11β-Hydroxysteroid Dehydrogenase Type 1

• DOI: 10.1021/jm025530f
• Publication Date: 2002-09-17T20:41:22Z
• Authors: Tjeerd Barf; Jerk Vallgårda; Rikard Emond; Charlotta Häggström; Guido Kurz; Alf Nygren; Vivienne Larwood; Erifili Mosialou; Kent Axelsson; Rolf Olsson; Lars Engblom; Naimie Edling; Yuko Rönquist-Nii; Birgitta Öhman; Peteris Alberts; Lars Abrahmsén
• Keywords: Blood Glucose; Sulfonamides; 0303 health sciences; Hydroxysteroid Dehydrogenases; 3. Good health; Mice; Structure-Activity Relationship; Thiazoles; 03 medical and health sciences; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Humans; Hypoglycemic Agents

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.