Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-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 (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.
Barf
Tjeerd
T
Department of Medicinal Chemistry, Biovitrum, Box 6443, SE-751 37, Uppsala, Sweden. tjeerd.barf@biovitrum.com
Vallgårda
Jerk
J
Emond
Rikard
R
Häggström
Charlotta
C
Kurz
Guido
G
Nygren
Alf
A
Larwood
Vivienne
V
Mosialou
Erifili
E
Axelsson
Kent
K
Olsson
Rolf
R
Engblom
Lars
L
Edling
Naimie
N
Rönquist-Nii
Yuko
Y
Ohman
Birgitta
B
Alberts
Peteris
P
Abrahmsén
Lars
L
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013449:Sulfonamides; D013844:Thiazoles; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human