title: Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist.
abstract: Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development L.L.C., Drug Discovery, 1000 Route 202, Raritan, NJ 08869, USA. wjiang1@prdus.jnj.com
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: James J
authors.initials: JJ
authors.lastname: Fiordeliso
authors.forename: George
authors.initials: G
authors.lastname: Allan
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Pamela
authors.initials: P
authors.lastname: Tannenbaum
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Peifang
authors.initials: P
authors.lastname: Zhu
authors.forename: Joseph
authors.initials: J
authors.lastname: Gunnet
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D000818:Animals; D001682:Biological Availability; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005951:Glucose Tolerance Test; D006801:Humans; D020128:Inhibitory Concentration 50; D015735:Mifepristone / Q000494:pharmacology; D010758:Phosphorus; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
chemical_list: D011965:Receptors, Glucocorticoid; D013256:Steroids; D010758:Phosphorus; D015735:Mifepristone