Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs.: Discovery of potent and selective inhibitors of the 11β-hydroxysteroid dehydrogenase type 1

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 (IC50 = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC50 = 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(gamma) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.(C) 2002 American Chemical Society