Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists.
An approach to the computer-assisted, pharmacophore design of nonsteroidal templates for the glucocorticoid receptor (GR) that contained an element of pseudo-C2 symmetry was developed. The enatiomer of the initial design, 1Ra, and not the designed molecule, 1S, showed the desired ligand binding to the GR. The pseudo-C2 symmetry of the template allowed for rapid improvements in GR activity resulting in potent, selective, nonsteroidal GR antagonists, CP-394531 and CP-409069.
Morgan
Bradley P
BP
Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06371, USA. bmorgan@cytokinetics.com
Swick
Andrew G
AG
Hargrove
Diane M
DM
LaFlamme
Janet A
JA
Moynihan
Melinda S
MS
Carroll
Richard S
RS
Martin
Kelly A
KA
Lee
Eunsun
E
Decosta
Debra
D
Bordner
Jon
J
D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
C458020:4a-benzyl-2-chloroethynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol; C458019:4a-benzyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol; D008024:Ligands; D010616:Phenanthrenes; D011965:Receptors, Glucocorticoid