Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
Clackers
Margaret
M
Medicines Research Centre, riCEDD, GlaxoSmithKline, Stevenage, UK.
Coe
Diane M
DM
Demaine
Derek A
DA
Hardy
George W
GW
Humphreys
Davina
D
Inglis
Graham G A
GG
Johnston
Michael J
MJ
Jones
Haydn T
HT
House
David
D
Loiseau
Richard
R
Minick
Doug J
DJ
Skone
Philip A
PA
Uings
Iain
I
McLay
Iain M
IM
Macdonald
Simon J F
SJ
D000577:Amides / Q000737:chemistry; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000819:agonists*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D011720:Pyrazoles / Q000737:chemistry*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry
D000577:Amides; D005938:Glucocorticoids; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; D013256:Steroids