| Literature DB >> 29424542 |
Lena Ripa1, Karl Edman2, Matthew Dearman1, Goran Edenro1, Ramon Hendrickx1, Victoria Ullah1, Hui-Fang Chang1, Matti Lepistö1, Dave Chapman1, Stefan Geschwindner2, Lisa Wissler2, Petter Svanberg1, Karolina Lawitz3, Jesper Malmberg1, Antonios Nikitidis1, Roine I Olsson1, James Bird1, Antoni Llinas1, Tove Hegelund-Myrbäck1, Markus Berger4, Philip Thorne5, Richard Harrison5, Christian Köhler2, Tomas Drmota1.
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.Entities:
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Year: 2018 PMID： 29424542 DOI： 10.1021/acs.jmedchem.7b01690
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446