Synthesis of Enantiospecific Androgen Receptor Antagonists of Enzalutamide-Resistant Human Prostate Cancer Cells

Abstract Drugs targeting the androgen receptor (AR) are important therapeutics for castration-resistant prostate cancer (CRPC) but are vulnerable to resistance due to AR mutations. Previously, we reported that the (5R/5S) enantiomer pairs of four novel 3-pyrrolazole carboxamide derivatives 9ab–12ab are antagonists and agonists, respectively, of AR, as demonstrated by transcriptional assays supported by fluorescence microscopy and proliferation studies. Herein, we describe the synthesis and stereochemical characterization of these compounds and document their enantiospecific effect on enzalutamide-resistant AR.