Discovery and optimisation of a selective non-steroidal 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. H...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 137 - 140 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Amsterdam
Elsevier Ltd
01.01.2011
Elsevier |
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| Abstract | 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. |
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| AbstractList | High-throughput screening of 3.87 million 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. 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. |
| Author | Thomson, Fiona Smith, Alasdair Brown, Angus R. Kingsbury, Celia Mistry, Ashvin Cowley, Angela Firth, Alistair McIntosh, Lorraine Cameron, Helen Grove, Simon J.A. Clark, John Hamilton, Niall M. Grant, Emma Rankovic, Zoran Nimz, Olaf Sherborne, Brad Craighead, Mark Grassie, Morag Lusher, Scott J. Bosies, Michael Kiczun, Michael Ohlmeyer, Michael Littlewood, Peter T.A. Weston, Mark Hampson, Hannah Spinks, Gayle Watson, Lynn Hillier, Alison Elmore, Moira A. Speake, Michael Ho, Koc-Kan Goutcher, Susan Kultgen, Steven G. MacDonald, Susan Pick, Jack Goodwin, Richard McIntyre, Theresa Morphy, J. Richard |
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| Keywords | 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 |
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| References | b0080 Robak, Herbage, Ellman (b0070) 2010; 110 Johanssen, Allolio (b0045) 2007; 157 b0050 Hu, Bolten (b0025) 2006; 67 Schweitzer, Knauer, Stauber (b0010) 2008; 18 . Tomlinson, Stewart (b0030) 2007; 21 Clark (b0035) 2008; 8 Mangelsdorf, Thummel, Beato, Herrlich, Schutz, Umesono, Blumberg, Kastner, Mark, Chambon, Evans (b0005) 1995; 83 b0055 Bengtson, Hallberg, Larhed (b0065) 2002; 4 b0075 Fitzsimons, van Hooijdonk, Morrow, Peeters, Hamilton, Craighead, Vreugdenhil (b0040) 2009; 9 Schteingart (b0020) 2009; 14 Schweitzer (10.1016/j.bmcl.2010.11.054_b0010) 2008; 18 Clark (10.1016/j.bmcl.2010.11.054_b0035) 2008; 8 10.1016/j.bmcl.2010.11.054_b0015 Schteingart (10.1016/j.bmcl.2010.11.054_b0020) 2009; 14 Mangelsdorf (10.1016/j.bmcl.2010.11.054_b0005) 1995; 83 Fitzsimons (10.1016/j.bmcl.2010.11.054_b0040) 2009; 9 Johanssen (10.1016/j.bmcl.2010.11.054_b0045) 2007; 157 Bengtson (10.1016/j.bmcl.2010.11.054_b0065) 2002; 4 Robak (10.1016/j.bmcl.2010.11.054_b0070) 2010; 110 Hu (10.1016/j.bmcl.2010.11.054_b0025) 2006; 67 Tomlinson (10.1016/j.bmcl.2010.11.054_b0030) 2007; 21 |
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| Snippet | High-throughput screening of 3.87million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed... High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed... |
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| SubjectTerms | 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 |
| Title | Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist |
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