Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity.
A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.
Smith
Cameron J
CJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. cameron_smith@merck.com
Ali
Amjad
A
Balkovec
James M
JM
Graham
Donald W
DW
Hammond
Milton L
ML
Patel
Gool F
GF
Rouen
Gregory P
GP
Smith
Scott K
SK
Tata
James R
JR
Einstein
Monica
M
Ge
Lan
L
Harris
Georgianna S
GS
Kelly
Theresa M
TM
Mazur
Paul
P
Thompson
Chris M
CM
Wang
Chuanlin F
CF
Williamson
Joanne M
JM
Miller
Douglas K
DK
Pandit
Shilpa
S
Santoro
Joseph C
JC
Sitlani
Ayesha
A
Yamin
Ting-Ting D
TT
O'Neill
Edward A
EA
Zaller
Dennis M
DM
Carballo-Jane
Ester
E
Forrest
Michael J
MJ
Luell
Silvi
S
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D008024:Ligands; D011965:Receptors, Glucocorticoid