2. Academic Validation
  3. Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists

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

  • Eur J Med Chem. 2020 Apr 15;192:112196. doi: 10.1016/j.ejmech.2020.112196.
Xi Xu 1,  Qianming Du 2,  Ying Meng 1,  Zhiyu Li 3,  Hongxi Wu 4,  Yan Li 4,  Zhili Zhao 4,  Raoling Ge 1,  Xiaoyu Lu 5,  Siqi Xue 5,  Xijing Chen 5,  Yong Yang 4,  Jubo Wang 1,  Jinlei Bian 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China.
  • 5 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
  • 6 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 32169785 DOI: 10.1016/j.ejmech.2020.112196
Abstract

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.

Keywords

Androgen receptor; Brain-blood barrier; Prostate cancer; Pyridine tetrahydroisoquinoline thiohydantoin.

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