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

Keith Biggadike; Matilde Caivano; Margaret Clackers; Diane M Coe; George W Hardy; Davina Humphreys; Haydn T Jones; David House; Annette Miles-Williams; Philip A Skone; Iain Uings; Vicki Weller; Iain M McLay; Simon J F Macdonald

doi:10.1016/j.bmcl.2009.06.020

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

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4846-50. doi: 10.1016/j.bmcl.2009.06.020. Epub 2009 Jun 13.

Authors

Keith Biggadike¹, Matilde Caivano, Margaret Clackers, Diane M Coe, George W Hardy, Davina Humphreys, Haydn T Jones, David House, Annette Miles-Williams, Philip A Skone, Iain Uings, Vicki Weller, Iain M McLay, Simon J F Macdonald

Affiliation

¹ Medicines Research Centre, Respiratory CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.

PMID: 19592247
DOI: 10.1016/j.bmcl.2009.06.020

Abstract

Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB 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.

MeSH terms

Catalytic Domain
Cell Line
Computer Simulation
Humans
Indazoles / chemistry
NF-kappa B / metabolism
Pyrazoles / chemistry*
Receptors, Glucocorticoid / agonists*
Receptors, Glucocorticoid / metabolism
Structure-Activity Relationship

Substances

Indazoles
NF-kappa B
Pyrazoles
Receptors, Glucocorticoid