Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile
| Autor: | Dave Chapman, Victoria Ullah, Lisa Wissler, James Bird, Jesper Malmberg, Petter Svanberg, Christian Köhler, Antonios Nikitidis, Matti Lepistö, Stefan Geschwindner, Karl Edman, Tomas Drmota, Lena Ripa, Richard P. Harrison, Hui-Fang Chang, Goran Edenro, Tove Hegelund-Myrbäck, Ramon Hendrickx, Roine I. Olsson, Matthew Dearman, Philip Thorne, Antoni Llinas, Karolina Lawitz, Markus Berger |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Indazoles Side effect medicine.drug_class Pyridines Anti-Inflammatory Agents Administration Oral Pharmacology Ligands Partial agonist Cell Line 03 medical and health sciences 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid In vivo Drug Discovery medicine Glucose homeostasis Animals Humans Receptor Chemistry Rats 030104 developmental biology 030220 oncology & carcinogenesis Prednisolone Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(5) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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