Background: Glucocorticoids are the most potent anti-inflammatory drugs available and allow successful treatment of several chronic inflammatory and autoimmune diseases. The discovery of the molecular mechanisms of the glucocorticoid receptor (GR), and the recognition that activation and repression of gene expression could be addressed separately, opened the possibility of improving safety profiles by identifying ligands that predominantly induce repression over activation. Recent progress in the development of dissociated and other non-steroidal GR modulators is discussed here. Objective: To summarize the data and progress of current compounds reported in GR programs carried out by pharmaceutical companies. Methods: The review is primarily of patents and publications disclosed over the last two years. Results/conclusion: Although the mechanistic drivers for development of safer GR ligands have expanded from the basic transrepression/transactivation hypothesis, the concept appears to have led to the identification of some drug candidates that show dissociated in vitro profiles and improved in vivo therapeutic indices.
