Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist.
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.
Jiang
Weiqin
W
Johnson & Johnson Pharmaceutical Research & Development L.L.C., Drug Discovery, 1000 Route 202, Raritan, NJ 08869, USA. wjiang1@prdus.jnj.com
Fiordeliso
James J
JJ
Allan
George
G
Linton
Olivia
O
Tannenbaum
Pamela
P
Xu
Jun
J
Zhu
Peifang
P
Gunnet
Joseph
J
Demarest
Keith
K
Lundeen
Scott
S
Sui
Zhihua
Z
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
D011965:Receptors, Glucocorticoid; D013256:Steroids; D010758:Phosphorus; D015735:Mifepristone