Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists.
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.
Biggadike
Keith
K
Medicines Research Centre, Respiratory CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
Caivano
Matilde
M
Clackers
Margaret
M
Coe
Diane M
DM
Hardy
George W
GW
Humphreys
Davina
D
Jones
Haydn T
HT
House
David
D
Miles-Williams
Annette
A
Skone
Philip A
PA
Uings
Iain
I
Weller
Vicki
V
McLay
Iain M
IM
Macdonald
Simon J F
SJ
D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007191:Indazoles; D016328:NF-kappa B; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid