Glucocorticoids (GCs) are the most commonly used anti-inflammatory and immunosuppressive drugs. Their efficacy seems to be caused by the interference of the ligand-activated glucocorticoid receptor (GR) with many pro-inflammatory pathways via different mechanisms. The ubiquitous expression of the GR is a prerequisite of this efficacy. The main draw back of GCs, however, is due to their potential to induce undesired effects, in particular upon high doses and prolonged usage. Introduction of topical GCs, that act locally, in the treatment of e.g. inflammatory skin diseases led to a reduction of systemic adverse effects. Nevertheless, undesirable cutaneous effects such as skin atrophy persist from the use of topical GCs. Therefore, a high medical need exists for drugs as effective as GCs but with a reduced side effect profile. Glucocorticoids function by binding to and activating the GR, which positively or negatively regulates the expression of specific genes. Several experiments suggest that negative regulation of gene expression (transrepression) by the GR accounts for its anti-inflammatory action. This occurs through direct or indirect binding of the receptor to pro-inflammatory transcription factors that are already bound to their regulatory sites. The positive action of the receptor (transactivation) occurs through homodimer binding of the ligand receptor complex to discrete nucleotide sequences and this contributes to some of the adverse effects of the hormone. Glucocorticoid receptor ligands that promote the negative regulatory action of the receptor with reduced positive regulatory function should therefore show an improved therapeutic index.
Consequently, our goal has been to identify GR ligands, which preferentially induce transrepression with little transactivation only.
Here, we show a representative of a novel class of compounds, selective glucocorticoid receptor agonists (SEGRAs), with a dissociation of transactivation from transrepression activity in vitro and in vivo. These non-steroidal GR-agonists represent promising new structures with improved effect/side effect profile.