Octahydrophenanthrene-2,7-diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration.
As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Robinson
Ralph P
RP
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. ralph.p.robinson@pfizer.com
Buckbinder
Leonard
L
Haugeto
Amber I
AI
McNiff
Patricia A
PA
Millham
Michele L
ML
Reese
Matthew R
MR
Schaefer
Jean F
JF
Abramov
Yuriy A
YA
Bordner
Jon
J
Chantigny
Yves A
YA
Kleinman
Edward F
EF
Laird
Ellen R
ER
Morgan
Bradley P
BP
Murray
John C
JC
Salter
Eben D
ED
Wessel
Matthew D
MD
Yocum
Sue A
SA
D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D013058:Mass Spectrometry; D008958:Models, Molecular; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists*
D010616:Phenanthrenes; D011965:Receptors, Glucocorticoid