Cortisol and the related cortisone and corticosterone are steroid hormones that are referred to as glucocorticoids (GCs) and bind to the glucocorticoid receptor (GR), which belongs to a large family of transcription factors, the superfamily of nuclear hormone receptors. GCs play an important role in the regulation of the immune system and therefore are widely used in the treatment of inflammatory and immune diseases such as rheumatoid arthritis, asthma, allergy, and sepsis. Synthetic GCs, which differ from cortisol in their pharmacokinetics and pharmacodynamics, have been created with dexamethasone and prednisolone being among the most extensively used anti-inflammatory agents. However, because of harmful dose-limiting side effects and the occurrence of glucocorticoid resistance, the use of these drugs is limited. Side effects include weight gain, hypertension, muscle weakness, skin thinning, diabetes, and the most troublesome GC-induced osteoporosis leading to a weakening of the trabecular bone, which causes a significant increase in the risk of spine, hip, and rib fractures. Upon binding of GCs to GR, a conformational change is provoked leading to the release of GR from the chaperone complexes and unmasking of nuclear localization signals followed by translocation of the GR–ligand complex to the nucleus. There, it is thought to directly and indirectly induce the expression of a few hundred genes, which is largely cell-type specific. The precise molecular mechanism is highly complex and, despite an impressive amount of research, still only partially understood. However, a simplistic hypothesis, which is based on a series of experiments, has become broadly accepted among researchers aiming at GCs with reduced side effects. This hypothesis attributes the anti-inflammatory effects of GCs to the inhibition of gene transcription, referred to as transrepression, while making the activation of transcription, called transactivation, responsible for the majority of side effects. Mechanistically it was rationalized that transrepression involves the GR–ligand complex indirectly in the transcription process through its interaction in a monomeric form with transcription factors such as NF-κB and AP-1 resulting in the down-regulation of key cytokine inflammatory mediators such as TNF-α, IL-1, IL-2, and IL-6. The transactivation pathway directly involves homodimers of GR recognizing GR response elements (GREs) on the DNA resulting in the transcription of genes. While this hypothesis is experimentally poorly supported and partially even contradicted, it served as an appealing working model for drug discovery programs over the past decade. Several companies have invested intense research in the quest of identifying functionally selective, so-called “dissociated” synthetic glucocorticoids with the goal of offering a therapeutic advantage over currently marketed GCs.¹

Human glucocorticoid receptor with bound agonist (PDB code: 3k23)