AI Article Synopsis
- Synthetic glucocorticoids are crucial for treating inflammatory diseases but can cause side effects like disrupted glucose levels and bone health.
- Researchers created partial agonists from a nonsteroidal GR ligand, focusing on improving therapeutic effects while minimizing adverse effects.
- The most promising compound, AZD9567, showed strong anti-inflammatory results in animal tests and is currently being compared to prednisolone in clinical trials.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.7b01690 | DOI Listing |
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