Novel thiohydantoin analogues bearing the 1-hydroxyl-2,2,2-trifluoro-1-ethyl moiety as androgen receptor inhibitors for the potential treatment of castration resistant prostate cancer

Enzalutamide (ENT) is an approved drug for the treatment of castration resistant prostate cancer (CRPC). Despite its success, the duration of response in patients is still limited with drug resistance. More robust CRPC drugs with novel structural motifs are urgently needed. Here, we designed and synthesized a series of 1-hydroxyl or 1-amino-2,2,2-trifluoro-1-ethyl compounds as isosteres to replace the amide group of ENT. Among the compounds prepared and tested, compund 13b is 2-fold more potent than ENT against LNCaP-AR cells. Western blot analysis showed that 13b dose-dependently inhibits the expression of the prostate-specific antigen (PSA). Further in vivo efficacy studies established that 13b has anti-tumor activity with oral administration at 15 mg kg −1 once daily.