2‑Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists

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.