Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity
Joint Authors
Hamzah, Ahmad Sazali
Pichika, Mallikarjuna Rao
Rathinasabapathy, Thirumurugan
Palatini Jackson, Kimberly Marie
Thor, Yiwen
Buru, Ayuba Sunday
Esposito, Debora
Li, Xu
Komarnytsky, Slavko
Source
Issue
Vol. 2017, Issue 2017 (31 Dec. 2017), pp.1-10, 10 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2017-03-29
Country of Publication
Egypt
No. of Pages
10
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Rathinasabapathy, Thirumurugan& Palatini Jackson, Kimberly Marie& Thor, Yiwen& Buru, Ayuba Sunday& Esposito, Debora& Li, Xu…[et al.]. 2017. Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity. Journal of Chemistry،Vol. 2017, no. 2017, pp.1-10.
https://search.emarefa.net/detail/BIM-1171645
Modern Language Association (MLA)
Rathinasabapathy, Thirumurugan…[et al.]. Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity. Journal of Chemistry No. 2017 (2017), pp.1-10.
https://search.emarefa.net/detail/BIM-1171645
American Medical Association (AMA)
Rathinasabapathy, Thirumurugan& Palatini Jackson, Kimberly Marie& Thor, Yiwen& Buru, Ayuba Sunday& Esposito, Debora& Li, Xu…[et al.]. Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity. Journal of Chemistry. 2017. Vol. 2017, no. 2017, pp.1-10.
https://search.emarefa.net/detail/BIM-1171645
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1171645