Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists

The discovery of 38E1 as a highly potent non-steroidal glucocorticoid agonist is described. Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFκB agonist activity was optimised in an iterative process from pIC 50 7.5 (for 7), to pIC 50 10.1 (for 38E1). An explanatio...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4846-4850
Hauptverfasser:	Biggadike, Keith, Caivano, Matilde, Clackers, Margaret, Coe, Diane M., Hardy, George W., Humphreys, Davina, Jones, Haydn T., House, David, Miles-Williams, Annette, Skone, Philip A., Uings, Iain, Weller, Vicki, McLay, Iain M., Macdonald, Simon J.F.
Format:	Artikel
Sprache:	eng
Schlagworte:	Agonist Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Catalytic Domain Cell Line Computer Simulation Glucocorticoid Hormones. Endocrine system Humans Indazoles - chemistry Medical sciences NF-kappa B - metabolism Non-steroidal Pharmacology. Drug treatments Pyrazoles - chemistry Receptors, Glucocorticoid - agonists Receptors, Glucocorticoid - metabolism Structure-Activity Relationship Tractable
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Zusammenfassung:	The discovery of 38E1 as a highly potent non-steroidal glucocorticoid agonist is described. Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFκB agonist activity was optimised in an iterative process from pIC 50 7.5 (for 7), to pIC 50 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.06.020