Synthesis and Pharmacological Evaluation of Novel Arylpiperazine Derivatives as Nonsteroidal Androgen Receptor Antagonists.

The search for novel antiandrogens by high-throughput screening (HTS) of the Yamanouchi chemical library led to the discovery of the lead compound (5), which possesses an arylmorpholine moiety. Through the optimization of the lead compound (5), we have found a series of novel arylpiperazine derivatives. Among them, 4-[4-cyano-(3-trifluoromethyl)phenyl]-N-(4-fluorophenyl)piperazine-1-carboxamide (22; YM-92088) exhibited a potent AR antagonistic activity with an IC50 value of 0.47 μM in the reporter assay, which is more potent than bicalutamide (4) which has an IC50 value of 0.89 μM.