title: Octahydrophenanthrene-2,7-diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration.
abstract: 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.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. ralph.p.robinson@pfizer.com
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: Amber I
authors.initials: AI
authors.lastname: Haugeto
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McNiff
authors.forename: Michele L
authors.initials: ML
authors.lastname: Millham
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.forename: Jean F
authors.initials: JF
authors.lastname: Schaefer
authors.forename: Yuriy A
authors.initials: YA
authors.lastname: Abramov
authors.forename: Jon
authors.initials: J
authors.lastname: Bordner
authors.forename: Yves A
authors.initials: YA
authors.lastname: Chantigny
authors.forename: Edward F
authors.initials: EF
authors.lastname: Kleinman
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.forename: John C
authors.initials: JC
authors.lastname: Murray
authors.forename: Eben D
authors.initials: ED
authors.lastname: Salter
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wessel
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
mesh_terms: 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*
chemical_list: D010616:Phenanthrenes; D011965:Receptors, Glucocorticoid