jm7b01690_si_001.csv (4.42 kB)
Download file

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

Download (4.42 kB)
dataset
posted on 09.02.2018, 00:00 by Lena Ripa, Karl Edman, Matthew Dearman, Goran Edenro, Ramon Hendrickx, Victoria Ullah, Hui-Fang Chang, Matti Lepistö, Dave Chapman, Stefan Geschwindner, Lisa Wissler, Petter Svanberg, Karolina Lawitz, Jesper Malmberg, Antonios Nikitidis, Roine I. Olsson, James Bird, Antoni Llinas, Tove Hegelund-Myrbäck, Markus Berger, Philip Thorne, Richard Harrison, Christian Köhler, Tomas Drmota
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.

History