Parallel strategies for the preparation and selection of liver-targeted glucocorticoid receptor antagonists.
Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.
Backes
Bradley J
BJ
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com
Hamilton
Gregory L
GL
Nguyen
Phong
P
Wilcox
Denise
D
Fung
Steven
S
Wang
Jiahong
J
Grynfarb
Marlena
M
Goos-Nilsson
Annika
A
Jacobson
Peer B
PB
von Geldern
Thomas W
TW
D000818:Animals; D005938:Glucocorticoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D015735:Mifepristone / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone