title: Parallel strategies for the preparation and selection of liver-targeted glucocorticoid receptor antagonists.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Hamilton
authors.forename: Phong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.forename: Steven
authors.initials: S
authors.lastname: Fung
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Marlena
authors.initials: M
authors.lastname: Grynfarb
authors.forename: Annika
authors.initials: A
authors.lastname: Goos-Nilsson
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
mesh_terms: 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*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone