Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.

前列腺癌（PC）是男性中最被诊断为恶性肿瘤的类型，并且是全世界范围内与癌症相关的死亡的主要原因。雄激素受体（AR）已成为治疗PC的有希望的药物靶标。在这里，我们报告了吡啶四氢异喹啉硫代乙内酰脲衍生物的设计，优化和评估，它们作为有效的AR拮抗剂具有更高的活性和安全性。最有前途的化合物42f对AR表现出强大的抑制活性，并强烈阻断了AR核的转运。此外，42f表现出对AR依赖的前列腺癌细胞系（LNCaP）有希望的体外抗肿瘤活性，并且还显示了对LNCaP异种移植小鼠模型（TGI：79％）的治疗作用，未观察到明显的毒性体内。更重要的是，与enzalutamide相比，42f显示出的血脑屏障（BBB）渗透率可忽略不计。这些结果为开发新型的雄激素受体拮抗剂提供了基础，该拮抗剂可用于潜在的抗PC疗法，对患者的精神分裂风险较低。