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

Abstract

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11β-HSD1 (IC₅₀ = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11β-HSD1 (IC₅₀ = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11β-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA^y mice, substantiating the 11β-HSD1 enzyme as a target for the treatment of type 2 diabetes.