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

doi:10.1016/j.bmc.2011.08.066

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

Molecular Bioinformatics

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	6383-6399
Number of pages	17
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	21
DOIs	https://doi.org/10.1016/j.bmc.2011.08.066
Publication status	Published - Nov 1 2011

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmc.2011.08.066

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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, 19(21), 6383-6399. https://doi.org/10.1016/j.bmc.2011.08.066

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

Research output: Contribution to journal › Article › peer-review

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

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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.",

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AU - Kusaka, Masami

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AU - Asahi, Satoru

AU - Furuya, Shuichi

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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

Abstract

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