title: 2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as potent dissociated glucocorticoid receptor agonists.
abstract: A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNFα production in human whole blood, with IC50 values (43-167 nM) approaching the level of DEX (21 nM). On the basis of X-ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2α phenyl, induced by the neighboring C3α methyl.
authors.forename: Yves A
authors.initials: YA
authors.lastname: Chantigny
authors.forename: John C
authors.initials: JC
authors.lastname: Murray
authors.forename: Edward F
authors.initials: EF
authors.lastname: Kleinman
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Plotkin
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McNiff
authors.forename: Michele L
authors.initials: ML
authors.lastname: Millham
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
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D010616:Phenanthrenes; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D053509:Matrix Metalloproteinase 13