Discovery of a potent series of non-steroidal non α-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity.
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
Epinova Discovery Performance Unit, Immuno-Inflammation CEDD, GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom. hawa.x.diallo@gsk.com
Hawa
H
Diallo
Davina C
DC
Angell
Heather A
HA
Barnett
Keith
K
Biggadike
Diane M
DM
Coe
Tony W J
TW
Cooper
Andy
A
Craven
James R
JR
Gray
David
D
House
Torquil I
TI
Jack
Steve P
SP
Keeling
Simon J F
SJ
Macdonald
Iain M
IM
McLay
Samuel
S
Oliver
Simon J
SJ
Taylor
Iain J
IJ
Uings
Natalie
N
Wellaway
D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D007191:Indazoles; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides