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Journal of Chemistry
Volume 2017, Article ID 3182129, 10 pages
Research Article

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

1Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
2Plants for Human Health Institute, North Carolina State University, North Carolina Research Campus, 600 Laureate Way, Kannapolis, NC 28081, USA
3Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, 400 Dan Allen Drive, Raleigh, NC 27695, USA
4Department of Animal Science, North Carolina State University, 120 Broughton Drive, Raleigh, NC 27695, USA
5Department of Plant and Microbial Biology, North Carolina State University, 100 Derieux Place, Raleigh, NC 27695, USA
6Center for Synthesis and Chemical Biology, Institute of Science, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia

Correspondence should be addressed to Slavko Komarnytsky; ude.uscn@ykstynramok

Received 25 December 2016; Revised 26 February 2017; Accepted 12 March 2017; Published 29 March 2017

Academic Editor: Shengmin Sang

Copyright © 2017 Thirumurugan Rathinasabapathy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.