Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 137 - 140
• Main Authors: Brown, Angus R., Bosies, Michael, Cameron, Helen, Clark, John, Cowley, Angela, Craighead, Mark, Elmore, Moira A., Firth, Alistair, Goodwin, Richard, Goutcher, Susan, Grant, Emma, Grassie, Morag, Grove, Simon J.A., Hamilton, Niall M., Hampson, Hannah, Hillier, Alison, Ho, Koc-Kan, Kiczun, Michael, Kingsbury, Celia, Kultgen, Steven G., Littlewood, Peter T.A., Lusher, Scott J., MacDonald, Susan, McIntosh, Lorraine, McIntyre, Theresa, Mistry, Ashvin, Morphy, J. Richard, Nimz, Olaf, Ohlmeyer, Michael, Pick, Jack, Rankovic, Zoran, Sherborne, Brad, Smith, Alasdair, Speake, Michael, Spinks, Gayle, Thomson, Fiona, Watson, Lynn, Weston, Mark
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: Animals; antagonists; Biological and medical sciences; chemistry; Drug Evaluation, Preclinical; Glucocorticoid receptor; glucocorticoid receptors; GR antagonist; High-Throughput Screening Assays; Hormones. Endocrine system; Humans; Hydrocortisone - chemistry; Medical sciences; Microsomes - metabolism; Nuclear receptor; Pharmacology. Drug treatments; Rats; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; screening; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; GR antagonist; Nuclear receptor; Glucocorticoid receptor; High throughput screening; Nitrile; Rat; Selectivity; Optimization; Pyridine derivatives; Structure activity relation; Pyrazole derivatives; Antagonist; Chemical synthesis; Non steroid compound; Biological receptor; Sulfonamide; Rodentia; In vitro; In vivo; Vertebrata; Mammalia; Animal; Benzenic compound; Fluorine Organic compounds; Pharmacokinetics; Absorption Distribution Metabolisme Excretion Toxicity; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.11.054

High-throughput screening of 3.87million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist. High-throughput screening of 3.87million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.