Discovery of non-steroidal mifepristone mimetics: pyrazoline-based PR antagonists.
Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-endometriotic activities. Non-steroidal mimetics of mifepristone and progesterone are important templates for modulation of the progesterone receptor (PR). For our PR program, we sought an unexplored, synthetically accessible non-steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. Docking of compounds into a PR homology model identified 4-substituted pyrazolines, which, when synthesized and tested, exhibited functional antagonism of PR.
Jones
David G
DG
GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA.
Liang
Xi
X
Stewart
Eugene L
EL
Noe
Robert A
RA
Kallander
Lara S
LS
Madauss
Kevin P
KP
Williams
Shawn P
SP
Thompson
Scott K
SK
Gray
David W
DW
Hoekstra
William J
WJ
D002460:Cell Line; D005456:Fluorescent Dyes; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection
D005456:Fluorescent Dyes; D008024:Ligands; D011720:Pyrazoles; D011980:Receptors, Progesterone; D015735:Mifepristone