Discovery of 7α-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure–activity relationships

Abstract

A series of 7α-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N- n-butyl- N-methyl amide ( 19a) showed pure antagonistic activity (IC 50 = 340 nM, FI 5 > 10,000 nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 ( CH4892280), which showed more potent pure antagonistic activity (IC 50 = 190 nM, FI 5 > 10,000 nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.