Discovery and structure–activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists

Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7α of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17α-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28–30, which showed pure antagonistic activities at submicromolar concentrations. The structure–activity relationships were clarified.