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DOI: 10.1055/a-2523-2752
Design, Synthesis, and Biological Evaluation of Thioether Steroids as Glucocorticoid Receptor Modulators
This work was funded by National Institutes of Health grants R01 DK123183 and R21 AI138136 to J.J.C., and by a University of Tennessee, Knoxville Science Fellowship to W.A.S., which was funded by the Tennessee Higher Education Commission.
Abstract
Glucocorticoids (GCs) are an important class of therapeutic steroids, commonly prescribed to treat inflammation and autoimmune disorders. However, long-term GC use can lead to serious metabolic complications including alterations in insulin sensitivity, resulting in an increased risk of diabetes. The antiinflammatory activity stems from GCs binding to the glucocorticoid receptor (GR) and functioning to oppose proinflammatory outcomes, while their undesired side effects arise through a variety of incompletely understood mechanisms. Previously, a set of thiobenzothiazole-modified GCs were shown to elicit modest antiinflammatory activity. In this study, a series of structurally diverse GC scaffolds were derivatized with thioheteroaryl moieties, and the products were biologically and computationally examined for their capacity to effectively engage the GR. Of the compounds studied, a C-21 thiobenzoxazole-substituted prednisolone analogue demonstrated a 56% reduction in 3x-GRE promoter reporter response and no loss in antiinflammatory potential.
Key words
glucocorticoids - antiinflammatory drugs - transrepression - transactivation - molecular dockingSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2523-2752.
- Supporting Information
Publikationsverlauf
Eingereicht: 25. November 2024
Angenommen nach Revision: 23. Januar 2025
Accepted Manuscript online:
23. Januar 2025
Artikel online veröffentlicht:
19. März 2025
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