Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist.
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Merck Research Laboratories (MSD), Newhouse, Motherwell, Lanarkshire ML1 5SH, UK. angus.brown@merck.com
Angus R
AR
Brown
Michael
M
Bosies
Helen
H
Cameron
John
J
Clark
Angela
A
Cowley
Mark
M
Craighead
Moira A
MA
Elmore
Alistair
A
Firth
Richard
R
Goodwin
Susan
S
Goutcher
Emma
E
Grant
Morag
M
Grassie
Simon J A
SJ
Grove
Niall M
NM
Hamilton
Hannah
H
Hampson
Alison
A
Hillier
Koc-Kan
KK
Ho
Michael
M
Kiczun
Celia
C
Kingsbury
Steven G
SG
Kultgen
Peter T A
PT
Littlewood
Scott J
SJ
Lusher
Susan
S
Macdonald
Lorraine
L
McIntosh
Theresa
T
McIntyre
Ashvin
A
Mistry
J Richard
JR
Morphy
Olaf
O
Nimz
Michael
M
Ohlmeyer
Jack
J
Pick
Zoran
Z
Rankovic
Brad
B
Sherborne
Alasdair
A
Smith
Michael
M
Speake
Gayle
G
Spinks
Fiona
F
Thomson
Lynn
L
Watson
Mark
M
Weston
D000818:Animals; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D006854:Hydrocortisone