Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer

Tomohiro Kaku, Takenori Hitaka, Akio Ojida, Nobuyuki Matsunaga, Mari Adachi, Toshimasa Tanaka, Takahito Hara, Masuo Yamaoka, Masami Kusaka, Teruaki Okuda, Satoru Asahi, Shuichi Furuya, Akihiro Tasaka

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17, 20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of la in the homology model of 17, 20-1yase, the 6, 7-dihydro-5H-pyrrolo[l, 2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17, 20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1 mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.

Original languageEnglish
Pages (from-to)6383-6399
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number21
DOIs
Publication statusPublished - Nov 1 2011

Fingerprint

Steroid 17-alpha-Hydroxylase
Prostatic Neoplasms
Derivatives
Phase III Clinical Trials
Dehydroepiandrosterone
Castration
Structure-Activity Relationship
Scaffolds
Haplorhini
Testosterone
Serum
orteronel
imidazole
naphthalene

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. / Kaku, Tomohiro; Hitaka, Takenori; Ojida, Akio; Matsunaga, Nobuyuki; Adachi, Mari; Tanaka, Toshimasa; Hara, Takahito; Yamaoka, Masuo; Kusaka, Masami; Okuda, Teruaki; Asahi, Satoru; Furuya, Shuichi; Tasaka, Akihiro.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 21, 01.11.2011, p. 6383-6399.

Research output: Contribution to journalArticle

Kaku, T, Hitaka, T, Ojida, A, Matsunaga, N, Adachi, M, Tanaka, T, Hara, T, Yamaoka, M, Kusaka, M, Okuda, T, Asahi, S, Furuya, S & Tasaka, A 2011, 'Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer', Bioorganic and Medicinal Chemistry, vol. 19, no. 21, pp. 6383-6399. https://doi.org/10.1016/j.bmc.2011.08.066
Kaku, Tomohiro ; Hitaka, Takenori ; Ojida, Akio ; Matsunaga, Nobuyuki ; Adachi, Mari ; Tanaka, Toshimasa ; Hara, Takahito ; Yamaoka, Masuo ; Kusaka, Masami ; Okuda, Teruaki ; Asahi, Satoru ; Furuya, Shuichi ; Tasaka, Akihiro. / Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 21. pp. 6383-6399.
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