Orteronel

Orteronel is a non-steroidal inhibitor of the 17,20-lyase activity of the cytochrome P450 (CYP) isoform CYP17A1 (IC₅₀s = 48 and 19 nM for the rat and human enzyme, respectively), which is the CYP17A1 activity that converts progestogens into androgens.¹ Orteronel is selective for the 17,20-lyase activity of CYP17A1 over its 11-hydroxylase activity and CYP3A4 (IC₅₀s = >1,000 and >10,000 nM, respectively). It decreases adrenocorticotropic hormone-induced production of DHEA, androstenedione, cortisol, and aldosterone in monkey adrenal cells (IC₅₀s = 110, 130, 310, and 4,400 nmol/L, respectively) and inhibits DHEA production in NCI-H295R human adrenocortical tumor cells.² A single oral dose of orteronel (0.3-10 mg/kg) dose-dependently decreases DHEA, cortisol, and testosterone levels in the plasma of intact cynomolgus monkeys for at least 10 hours, and chronic dosing of 15 mg/kg twice daily suppresses levels for up to seven days of treatment. It also decreases DHEA and testosterone plasma levels in castrated monkeys, indicating an effect on extra-gonadal production of testosterone.

WARNING This product is not for human or veterinary use.

1. Kaku, T., Hitaka, T., Ojida, A., et al. 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. 19(21), 6383-6399 (2011).

2. Yamaoka, M., Hara, T., Hitaka, T., et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: Effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J. Steroid. Biochem. Mol. Biol. 129(3-5), 115-128 (2012).