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

Autor:	Ripa L; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Edman K; Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden., Dearman M; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Edenro G; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Hendrickx R; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Ullah V; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Chang HF; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Lepistö M; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Chapman D; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Geschwindner S; Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden., Wissler L; Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden., Svanberg P; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Lawitz K; AstraZeneca R&D Lund , Scheelevägen 1 , Lund 22187 , Sweden., Malmberg J; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Nikitidis A; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Olsson RI; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Bird J; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Llinas A; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Hegelund-Myrbäck T; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden., Berger M; Medicinal Chemistry Berlin, Drug Discovery, Pharmaceuticals , Bayer AG , Berlin 13353 , Germany., Thorne P; AstraZeneca R&D Charnwood , Bakewell Road , Loughborough , Leicestershire LE11 5RH , U.K., Harrison R; AstraZeneca R&D Charnwood , Bakewell Road , Loughborough , Leicestershire LE11 5RH , U.K., Köhler C; Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden., Drmota T; Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Mar 08; Vol. 61 (5), pp. 1785-1799. Date of Electronic Publication: 2018 Feb 16.
DOI:	10.1021/acs.jmedchem.7b01690
Abstrakt:	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:	MEDLINE
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