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

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 increased risk for diabetes. The anti-inflammatory activity stems from GCs binding to the glucocorticoid receptor (GR) and functioning to oppose pro-inflammatory 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 anti-inflammatory activity. In this study, a series of structurally diverse GC scaffolds were derivatized with thio-heteroaryl moieties and 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 anti-inflammatory potential.