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

Xi Xu; Qianming Du; Ying Meng; Zhiyu Li; Hongxi Wu; Yan Li; Zhili Zhao; Raoling Ge; Xiaoyu Lu; Siqi Xue; Xijing Chen; Yong Yang; Jubo Wang; Jinlei Bian

doi:10.1016/j.ejmech.2020.112196

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. Epub 2020 Mar 5.

Authors

Xi Xu¹, Qianming Du², Ying Meng¹, Zhiyu Li³, Hongxi Wu⁴, Yan Li⁴, Zhili Zhao⁴, Raoling Ge¹, Xiaoyu Lu⁵, Siqi Xue⁵, Xijing Chen⁵, Yong Yang⁴, Jubo Wang¹, Jinlei Bian⁶

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.

MeSH terms

Androgen Receptor Antagonists / chemical synthesis
Androgen Receptor Antagonists / chemistry
Androgen Receptor Antagonists / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Blood-Brain Barrier / drug effects*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Receptors, Androgen / metabolism*
Structure-Activity Relationship
Tetrahydroisoquinolines / chemical synthesis
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology*
Thiohydantoins / chemical synthesis
Thiohydantoins / chemistry
Thiohydantoins / pharmacology*
Tumor Cells, Cultured

Substances

Androgen Receptor Antagonists
Antineoplastic Agents
Pyridines
Receptors, Androgen
Tetrahydroisoquinolines
Thiohydantoins
pyridine