Glucocorticoids (GCs) are the most commonly used anti-inflammatory and immunosuppressive drugs. GCs possess outstanding therapeutic effects, however, severe and sometimes irreversible side effects always accompany them. Therefore, it is urgent to develop new drugs which have a reduced side-effect profile. Meanwhile, maintaining the anti-inflammatory and immunosuppressive properties of classical GCs.
GCs bind to the GC receptor (GR) after entry into target cells. Then it translocates into the nucleus to regulate gene transcription directly or indirectly.
The ligand-activated GR binds as a homodimer to consensus sequences. It induces transcription (transactivation) of genes such as tyrosine aminotransferase (TAT). Besides, the ligand-activated receptor binds as a monomer to transcription factors to inhibit the activity of many proinflammatory transcription factors. This transrepression is the main mechanism for the anti-inflammatory activity of GCs. In contrast, several side effects are thought to be predominantly mediated via transactivation.
In this article, we will introduce a nonsteroidal selective glucocorticoid receptor agonist, ZK 216348. It binds to Progesterone and mineralocorticoid receptors with IC50s of 20.4 nM and 79.9 nM, respectively.
Firstly, In human peripheral blood mononuclear cells (PBMCs), ZK 216348 can inhibit LPS-stimulated TNF-α and IL-12 production, with IC50 values of 89 nM and 52 nM, respectively. Moreover, in Caco-2 cells, ZK 216348 also suppresses the TNF-α-induced expression of the proinflammatory cytokine IL-8. Those results indicate that ZK 216348 participate in an active GR in the anti-inflammatory response.
Nextly, In the croton oil mouse model of ear inflammation, ZK 216348 shows comparable potency regarding the inhibition of ear edema (ED50: 0.02 μg/cm2) and granulocyte infiltration in a peroxidase activity assay (ED50: 0.03 μg/cm2).
In rats, ZK 216348 inhibits ear edema similarly to PRED (Prednisolone) in both mice (ED50: 2 mg/kg SEGRA, 9 mg/kg PRED) and rats (ED50: 2 mg/kg SEGRA, 3.5 mg/kg PRED).
In conclusion, ZK 216348 is a novel and potent SEGRA, representing a compound class with an improved therapeutic index when it compares to classical GCs. Moreover, this kind of compound has a reduced risk of developing certain side effects, such as diabetes mellitus. Therefore, the compound has the potential to be a tool to further investigate the molecular basis of GC side effects.
Schäcke H, et al. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):227-32.