Design, Synthesis, and Biological Evaluation of Thioether Steroids as Glucocorticoid Receptor Modulators

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.