Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile

Synthetic
glucocorticoids (GC) are essential for the treatment
of a broad range of inflammatory diseases. However, their use is limited
by target related adverse effects on, e.g., glucose homeostasis and
bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key
functional triggers within the receptor, generating a range of structurally
diverse partial agonists. Of these, only a narrow subset exhibited
full anti-inflammatory efficacy and a significantly reduced impact
on adverse effect markers in human cell assays compared to prednisolone.
This led to the discovery of AZD9567 (15) with excellent
in vivo efficacy when dosed orally in a rat model of joint inflammation.
Compound 15 is currently being evaluated in clinical
trials comparing the efficacy and side effect markers with those of
prednisolone.