title: Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06371, USA. bmorgan@cytokinetics.com
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Swick
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: Janet A
authors.initials: JA
authors.lastname: LaFlamme
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Moynihan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Martin
authors.forename: Eunsun
authors.initials: E
authors.lastname: Lee
authors.forename: Debra
authors.initials: D
authors.lastname: Decosta
authors.forename: Jon
authors.initials: J
authors.lastname: Bordner
mesh_terms: 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
chemical_list: 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