Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 
with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is 
synthesized from androgen by aromatase activity, and the effect of orteronel on 
estrogen synthesis was therefore evaluated. First, it was confirmed that 
orteronel does not directly inhibit aromatase activity. Second, the specific 
decline of serum estradiol and androgen levels in hypophysectomized female rats 
by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; 
orteronel at doses ≥3mg/kg significantly suppressed serum estradiol, 
testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased 
progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 
300mg/kg, suppressed serum estradiol concentrations to a similar degree as 
0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum 
aldosterone, corticosterone, and progesterone levels did not change 
significantly following administration of 300mg/kg of orteronel. Third, the 
effect of multiple oral administration of orteronel on serum estradiol levels in 
regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 
15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the 
estradiol surge prior to the start of luteal phase for 1.5-times the average 
duration of three consecutive, pre-treatment menstrual cycles, while serum 
progesterone was maintained at levels almost equal to those in the luteal phase 
although a certain portion of this increased level of progesterone could be of 
adrenal-origin. This suppressive effect on estradiol surge was thought to be 
reversible since serum estradiol levels started to rise immediately after the 
discontinuation of orteronel. Estradiol surge was not abrogated by treatment 
with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel 
can suppress serum estradiol concentrations in hypophysectomized female rats and 
monkeys through selective inhibition of CYP17A1 activity, suggesting that 
orteronel might be effective for hormone-dependent breast cancers and 
estrogen-dependent diseases.