Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of Potent and Selective Inhibitors of the 11β-Hydroxysteroid Dehydrogenase Type 1
- 1 August 2002
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 45 (18) , 3813-3815
- https://doi.org/10.1021/jm025530f
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 KKAy mice, substantiating the 11β-HSD1 enzyme as a target for the treatment of type 2 diabetes.Keywords
This publication has 5 references indexed in Scilit:
- Type 1 11β-Hydroxysteroid Dehydrogenase Mediates Glucocorticoid Activation and Insulin Release in Pancreatic IsletsJournal of Biological Chemistry, 2000
- Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2Journal of Clinical Investigation, 1999
- Selective inhibition of human type 1 11β‐hydroxysteroid dehydrogenase by synthetic steroids and xenobioticsFEBS Letters, 1998
- 11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stressProceedings of the National Academy of Sciences, 1997
- The metabolism of 9α-fluorinated steroids in the human kidneyEndocrine Research, 1996