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

CNS Drug Discovery Unit, Takeda Pharmaceutical Company, Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan.


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.

Written by:
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.   Are you the author?

Reference: Bioorg Med Chem. 2011 Nov 1;19(21):6383-99.
doi: 10.1016/j.bmc.2011.08.066

PubMed Abstract
PMID: 21978946 Investigational Urology Section