The glucocorticoid receptor (GR) is a ligand activated transcription factor. GR plays a fundamental role in regulating development, metabolism, inflammation, and stress response. GCs have been used to treat patients with rheumatoid arthritis (RA) for nearly 70 years. Furthermore, the use of synthetic GCs has transformed the treatment of inflammatory and autoimmune diseases. Increasing programs are discoverring safer GR ligands, and novel oral nonsteroidal ligands have been identified. A study from Lena Ripa, et al. discovered a novel oral GR modulator AZD9567 with improved side effect profile.
AZD9567 (compound 15) is a potent, selective and oral active non-steroidal glucocorticoid receptor modulator (SGRM) with an IC50 of 3.8 nM. It is well-known that GCs may cause off-target pharmacology due to lack of selectivity toward other closely related nuclear hormone receptors. However, AZD9567 is an exception. In TA assay, it showed to be a partial agonist. Therefore, it resulted in full GR translocation into the nucleus. In addition, the oral active compound showed excellent selectivity in a panel of >300 in vitro radio ligand binding and enzyme assays. Not only that, it also showed over 1000-fold selectivity over cardiovascular ion channels. Taken together, these data demonstrated that AZD9567 is a highly selective GR modulator with low risk for off-target effects.
In vivo, AZD9567 achieved a maximum plasma concentration of 2.0 μM at 2 h with a terminal half-life similar to that of prednisolone. Similarly in beagle dogs, it showed a bioavailability of 48%. Besides, this modulator exhibits excellent efficacy in the streptococcal cell wall (SCW) reactivation model of joint inflammation.
To conclude, the compound has potential to be a clinical candidate with low toxicity for related diseases.