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

  • J Med Chem. 2002 Aug 29;45(18):3813-5. doi: 10.1021/jm025530f.
Tjeerd Barf  1 ,  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 Ohman ,  Peteris Alberts ,  Lars Abrahmsén
Affiliations
  • 1. Department of Medicinal Chemistry, Biovitrum, Box 6443, SE-751 37, Uppsala, Sweden. [email protected]
PMID: 12190302 DOI: 10.1021/jm025530f
Abstract

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.

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