Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists

Kazumi Inoue, Ko Urushibara, Misae Kanai, Kei Yura, Shinya Fujii, Mari Ishigami-Yuasa, Yuichi Hashimoto, Shuichi Mori, Emiko Kawachi, Mio Matsumura, Tomoya Hirano, Hiroyuki Kagechika, Aya Tanatani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


The androgen receptor (AR) plays important roles in multiple physiological functions, including differentiation, growth, and maintenance of male reproductive organs, and also has effects on hair and skin. In this paper, we report the synthesis of nonsteroidal AR antagonists having a 4-benzyl-1-(2H)-phthalazinone skeleton. Among the synthesized compounds, 11c with two ortho-substituents on the phenyl group potently inhibited SC-3 cell proliferation (IC50: 0.18 μM) and showed high wt AR-binding affinity (IC50: 10.9 μM), comparable to that of hydroxyflutamide (3). Compound 11c also inhibited proliferation of LNCaP cells containing T877A-mutated AR. Docking study of 11c with the AR ligand-binding domain indicated that the benzyl group is important for the antagonism. These phthalazinone derivatives may be useful for investigating potential clinical applications of AR antagonists.

Original languageEnglish
Article number8038
Pages (from-to)310-319
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2015 Sept 18
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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