Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators.
The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f]quinoline core leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum substituent that imparts minimal GR mediated in vitro transcriptional activation while maintaining full transcriptional repression is described. The in vitro profile of these candidates in human cell assays relevant to the therapeutic window of glucocorticoid modulators is outlined.
Elmore
Steven W
SW
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. steve.elmore@abbott.com
Pratt
John K
JK
Coghlan
Michael J
MJ
Mao
Yue
Y
Green
Brian E
BE
Anderson
David D
DD
Stashko
Michael A
MA
Lin
Chun W
CW
Falls
Douglas
D
Nakane
Masaki
M
Miller
Loan
L
Tyree
Curtis M
CM
Miner
Jeffrey N
JN
Lane
Ben
B
D001667:Binding, Competitive / Q000235:genetics; D005938:Glucocorticoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013489:Suppression, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid