Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity

Background. glucocorticoid excess has been linked to clinical observations associated with the pathophysiology of metabolic syndrome. the intracellular glucocorticoid levels are primarily modulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-hsd1) enzyme that is highly expressed in key metabolic tissues including fat,liver,and the central nervous system. methods. in this study we synthesized a set of novel tetrahydrothiazolopyridine derivatives,tr-01-4,that specifically target 11β-hsd1 and studied their ability to interfere with the glucocorticoid and lipid metabolism in the 3t3-l1 adipocytes. results. based on the docking model and structure-activity relationships,tetrahydrothiazolopyridine derivatives tr-02 and tr-04 showed the highest potency against 11β-hsd1 by dose-dependently inhibiting conversion of cortisone to cortisol (ic50 values of 1.8 μm and 0.095 μm,resp.). incubation of fat cells with 0.1-10 μm tr-01-4 significantly decreased cortisone-induced lipid accumulation in adipocytes and suppressed 11β-hsd1 mrna expression. observed reduction in adipocyte fat stores could be partially explained by decreased expression levels of adipogenic markers (ppar-γ,ap2) and key enzymes of lipid metabolism,including fatty acid synthase (fas),hormone sensitive lipase (hsl),and lipoprotein lipase (lpl). conclusions. the tetrahydrothiazolopyridine moiety served as an active pharmacophore for inhibiting 11β-hsd1 and offered a novel therapeutic strategy to ameliorate metabolic alterations found in obesity and diabetes. © 2017 thirumurugan rathinasabapathy et al.