Endogenous androgens play a role in the development and progression of prostate 
cancer (PC), thus androgen suppression may offer an effective therapeutic 
strategy for this disease. Orteronel (TAK-700), 
6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide, 
is a novel, non-steroidal, selective inhibitor of the 17,20-lyase activity of 
CYP17A--a key enzyme in the production of steroidal hormones--and is being 
developed as a therapy for PC. The purpose of this study was to elucidate the 
inhibitory activity of orteronel, in particular its specificity for androgen 
synthesis enzymes, in male rats--an androgen-synthesis model that largely 
reflects this pathway in humans. Orteronel inhibited 17,20-lyase activity in 
rats with an IC(50) of 1200 nM but did not inhibit 17α-hydroxylase or 
11β-hydroxylase (CYP11B1) activity in rats at concentrations up to 10 μM. In 
cellular steroidogenesis assays using rat testicular cells, orteronel suppressed 
testosterone and androstenedione production with an IC(50) of 640 nM and 210 nM, 
respectively, but did not suppress either corticosterone or aldosterone 
production in rat adrenal cells at concentrations up to 30 μM. In addition, 
serum testosterone and androstenedione levels in human chorionic 
gonadotropin-injected hypophysectomized rats were significantly reduced by 
single oral administration of orteronel at a dose of 30 mg/kg (both p ≤ 0.01); 
serum corticosterone and aldosterone levels in ACTH-injected hypophysectomized 
rats did not result in significant differences compared with controls, following 
orteronel administration at doses up to 300 mg/kg. Serum testosterone levels in 
intact male rats were significantly reduced by orteronel 4h after dosing at 
100mg/kg (p ≤ 0.01); testosterone levels showed a tendency to recover afterward. 
In intact male rats, the weight of the prostate glands and seminal vesicles was 
decreased in a dose-dependent manner following multiple doses of orteronel at 
37.5, 150, and 600 mg/kg, TID for 4 days. The reversibility of orteronel was 
further confirmed using a human adrenocortical tumor cell line. In summary, 
orteronel is a selective and reversible 17,20-lyase inhibitor, and decreases the 
weight of androgen-dependent organs in male rats. Our data suggests that 
orteronel would therefore be effective for androgen-dependent disorders such as 
PC.