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

  • Bioorg Med Chem. 2011 Nov 1;19(21):6383-99. doi: 10.1016/j.bmc.2011.08.066.
Tomohiro Kaku  1 ,  Takenori Hitaka ,  Akio Ojida ,  Nobuyuki Matsunaga ,  Mari Adachi ,  Toshimasa Tanaka ,  Takahito Hara ,  Masuo Yamaoka ,  Masami Kusaka ,  Teruaki Okuda ,  Satoru Asahi ,  Shuichi Furuya ,  Akihiro Tasaka
Affiliations
  • 1. CNS Drug Discovery Unit, Takeda Pharmaceutical Company, Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan. [email protected]
PMID: 21978946 DOI: 10.1016/j.bmc.2011.08.066
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 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 1mg/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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