Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

摘要: Abstract A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from reported AR and in silico modeling. Within series, compound (R)-6 (ONC1–13B) its related analogues, including N-dealkylated metabolite, were found to be most potent molecules with target activity (IC50, androgen-sensitive human PCa LNCaP cells) range 59–80 nM (inhibition PSA production). The disclosed hits at least two times more than bicalutamide, nilutamide enzalutamide within performed assay. Several compounds classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles rats. Comparative 3D molecular docking for hit elucidating observed differences binding potency.