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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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC., (Copyright © 2012 Elsevier Ltd. All rights reserved.)