Synthetic glucocorticoids like prednisolone have been used for more than 50 years to treat inflammatory diseases however their use is limited by side effects including diabetes and osteoporosis. The aim of our oral glucocorticoid receptor (GR) modulator project was to identify an orally available dissociated glucocorticoid receptor modulator with improved therapeutic margins versus prednisolone. In the chemistry program we focused our design to find potent partial modulators of GR with the potential to sample the GR conformational space differently compared to glucocorticoids currently in use opening for the possibility of differentiated co-factor interactions, signaling and biological effects subsequently leading to the separation of desired and non-desired GR related effects. Utilizing full GR agonist indazole ethers as the starting point for design we have identified structural modifications that lead to compounds with potent but partial profile in GR reporter gene assays. Regardless of the compound profile in the reporter gene assays only a narrow subset of specific structural modifications lead to a beneficial biological response with respect to GR related side effects. This work led to the discovery of AZ9567 a potent anti-inflammatory compound with reduced side effects compared to prednisolone in in vitro cell systems and in in vivo rat models and currently is evaluated in clinical trials.

Identification of AZD9567, an anti-inflammatory glucocorticoid receptor modulator with improved side effect profile

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.