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

Abstract

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.

Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

“…By contrast, substantial changes in ligand structure can affect the interaction network within the protein, thereby rewiring the allosteric transmission pathway. Thus, ligands with different chemical scaffolds and pharmacophores may create new opportunities to influence the structural ensembles and communication pathways in unique ways that will be important to consider when developing mechanistically differentiating GR ligands ( 3 , 13 , 17 , 28 , 38 ).…”

“…To investigate whether the observed population shift of helix 12 conformations might correlate with the functional response of GR, we measured agonist efficacy in a transactivation reporter gene assay (Fig. 4) (28). The top effect relative to dex (100%) varies from 77% for dibC and cortisol, 86% for pred, to 90% for AZ938.…”

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

“…Ripa et al [ 102 ] designed a novel series of 1 H -indazole derivatives as potent glucocorticoid receptor (GR) modulators and conducted transactivation (TA) and transrepression (TR) assays. Based on the assays results, the compounds were further evaluated in functional assays measuring inhibition of lipopolysaccharide (LPS) induced tumor necrosis factor (TNF) α release in whole blood, upregulation of tyrosine aminotransferase (TAT) in primary hepatocytes, and downregulation of osteoprotegerin (OPG) in human fetal osteoblasts (hFOB).…”

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

“…Therefore, validation of an improved therapeutic benefit depends on representative animal models. While this is readily implemented for anti-inflammatory effect scoring, concomitant testing of side effect parameters (such as glucose tolerance, insulin tolerance, cortisol levels, bone mineral density) presents a bottleneck, because a longer treatment protocol may be needed to surpass the thresholds of measurable results for these parameters or because of species differences (see below) (22,43).…”