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

作者：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

来源：Bioorganic & Medicinal Chemistry, 2011, 19(21): 6383-6399.

DOI：10.1016/j.bmc.2011.08.066

• TAK-700
• 17,20-Lyase
• Prostate cancer
• Orteronel

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 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-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.

• 出版日期2011-11-1