Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

To further elucidate the structural
activity correlation of glucocorticoid
receptor (GR) antagonism, the crystal structure of the GR ligand-binding
domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in
vitro activity comparable to known GR antagonists such as mifepristone,
and notably, this molecule lowers LDL (−74%) and raises HDL
(+73%) in a hamster model of dyslipidemia. This is the first reported
crystal structure of the GR LBD bound to a nonsteroidal antagonist,
and this article provides additional elements for the design and pharmacology
of clinically relevant nonsteroidal GR antagonists that may have greater
selectivity and fewer side effects than their steroidal counterparts.