Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists.

We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 μM). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.