2017 journal article

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

JOURNAL OF CHEMISTRY, 2017.

co-author countries: Malaysia 🇲🇾 United States of America 🇺🇸
Source: Web Of Science
Added: August 6, 2018

Background . Glucocorticoid excess has been linked to clinical observations associated with the pathophysiology of metabolic syndrome. The intracellular glucocorticoid levels are primarily modulated by 11 β -hydroxysteroid dehydrogenase type 1 (11 β -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 11 β -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 11 β -HSD1 by dose-dependently inhibiting conversion of cortisone to cortisol (IC 50 values of 1.8 μ M and 0.095 μ M, resp.). Incubation of fat cells with 0.1–10 μ M TR-01–4 significantly decreased cortisone-induced lipid accumulation in adipocytes and suppressed 11 β -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 11 β -HSD1 and offered a novel therapeutic strategy to ameliorate metabolic alterations found in obesity and diabetes.