Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists

• Published in: European journal of medicinal chemistry 2020-04, Vol.192, p.112196-112196, Article 112196
• Main Authors: Xu, Xi, Du, Qianming, Meng, Ying, Li, Zhiyu, Wu, Hongxi, Li, Yan, Zhao, Zhili, Ge, Raoling, Lu, Xiaoyu, Xue, Siqi, Chen, Xijing, Yang, Yong, Wang, Jubo, Bian, Jinlei
• Format: Article
• Language: English
• Subjects: Androgen receptor; Brain-blood barrier; Prostate cancer; Pyridine tetrahydroisoquinoline thiohydantoin
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112196

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. [Display omitted] •A series of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as AR antagonists were reported.•The most promising compound 42f exhibited potent therapeutic effects in LNCaP xenograft tumor model (TGI: 79%) with no apparent toxicity.•42f showed negligible penetration of the BBB compared with enzalutamide.•These results provide a foundation for the development of a new class of androgen receptor antagonists with low seizurogenic risk.