PMID- 25706100
OWN - NLM
STAT- MEDLINE
DCOM- 20150526
LR  - 20150326
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 58
IP  - 6
DP  - 2015 Mar 26
TI  - 2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as potent dissociated 
      glucocorticoid receptor agonists.
PG  - 2658-77
LID - 10.1021/jm501601b [doi]
AB  - 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 TNFalpha 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 C2alpha phenyl, induced by the 
      neighboring C3alpha methyl.
FAU - Chantigny, Yves A
AU  - Chantigny YA
FAU - Murray, John C
AU  - Murray JC
FAU - Kleinman, Edward F
AU  - Kleinman EF
FAU - Robinson, Ralph P
AU  - Robinson RP
FAU - Plotkin, Michael A
AU  - Plotkin MA
FAU - Reese, Matthew R
AU  - Reese MR
FAU - Buckbinder, Leonard
AU  - Buckbinder L
FAU - McNiff, Patricia A
AU  - McNiff PA
FAU - Millham, Michele L
AU  - Millham ML
FAU - Schaefer, Jean F
AU  - Schaefer JF
FAU - Abramov, Yuriy A
AU  - Abramov YA
FAU - Bordner, Jon
AU  - Bordner J
LA  - eng
PT  - Journal Article
DEP - 20150317
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Interleukin-1)
RN  - 0 (Phenanthrenes)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 13)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Cell Line
MH  - Crystallography, X-Ray
MH  - Dexamethasone/pharmacology
MH  - Humans
MH  - Interleukin-1/immunology
MH  - Mammary Tumor Virus, Mouse/genetics
MH  - Matrix Metalloproteinase 13/genetics
MH  - Mice
MH  - Models, Molecular
MH  - Phenanthrenes/*chemistry/*pharmacology
MH  - Receptors, Glucocorticoid/*agonists/metabolism
MH  - Tumor Necrosis Factor-alpha/blood/immunology
MH  - Up-Regulation/drug effects
EDAT- 2015/02/24 06:00
MHDA- 2015/05/27 06:00
CRDT- 2015/02/24 06:00
PHST- 2015/02/24 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2015/05/27 06:00 [medline]
AID - 10.1021/jm501601b [doi]
PST - ppublish
SO  - J Med Chem. 2015 Mar 26;58(6):2658-77. doi: 10.1021/jm501601b. Epub 2015 Mar 17.