Identification of dissociated non-steroidal glucocorticoid receptor agonists.
A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.
Kuzmich
Daniel
D
Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. dkuzmich@rdg.boehringer-ingelheim.com
Kirrane
Tom
T
Proudfoot
John
J
Bekkali
Younes
Y
Zindell
Renee
R
Beck
Laura
L
Nelson
Richard
R
Shih
Cheng-Kon
CK
Kukulka
Alison J
AJ
Paw
Zofia
Z
Reilly
Patty
P
Deleon
Rodney
R
Cardozo
Mario
M
Nabozny
Gerald
G
Thomson
David
D
D005938:Glucocorticoids / Q000819:agonists*; D008024:Ligands; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D005938:Glucocorticoids; D008024:Ligands