CYP17A1 Inhibitor II, TAK-700

A cell-permeable, orally bioavailable (T_max/C_max/AUC = 1.7 h/147 ng·mL^-1/727 ng·h·mL^-1_{0-24 h}/monkey & 1.7 h/39 ng·mL^-1/177 ng·h·mL^-1_{0-8 h}/rat; 1 mg/kg p.o.), nonsteroidal, optically active naphthylmethylimidazole compound that acts as a potent, reversible, substrate-competitive inhibitor against the 17,20-lyase activity (IC₅₀/[substrate] = 19 nM/10 nM 17α-hydroxypregnenolone/rhP450c17, 27 nM/5 µM 17α-hydroxypregnenolone/monkey adrenal microsomes, 48 nM/10 nM 17α-hydroxyprogesterone /rat testicular microsomes, 140 nM/5 µM 17α-hydroxypregnenolone/rhP450c17, 1.2 µM/5 µM 17α-hydroxyprogesterone /rat testicular microsomes) of cytochrome P450 17A1 (CYP17A1; P450c17), while inhibiting only human & monkey, but not rat, CYP17A 17α-hydroxylase activity (IC₅₀/[substrate] = 38 nM/5 µM pregnenolone/monkey adrenal microsomes, 760 nM/5 µM pregnenolone/rhP450c17, >10 µM/5 µM progesterone/rat testicular microsomes) and exhibiting much reduced or little potency against 11β-hydroxylase activity (IC₅₀ >1 µM/rat testicular microsomes & >10 µM/monkey adrenal microsomes) or 9 other human CYP isoforms (IC₅₀ = 14 µM/2C19 & >30 µM/1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consistent with its enzyme inhibition activity, TAK-100 is shown to cause cellular progesterone built-up and reduce dehydroepiandrosterone (DHEA) & androstenedione production in human adrenocortical tumor cell NCI-H295R (IC₅₀ = 37 & 54 nM, respectively), ATCH-stimulated primary monkey adrenal cell (IC₅₀ = 110 & 130 nM, respectively), and hCG-stimulated primary rat testicular cell (IC₅₀ = 210 nM against androstenedione production) cultures with greater potency and selectivity than Ketoconazole (Cat. No. 420600). Oral administration is reported to result in reduced serum steroid levels in vivo among male cynomolgus monkeys (0.3 to 10 mg/kg for single & 3 to 15 mg/kg/12 h for multiple oral dosing) with or without castration and hypophysectomized male rats (30 to 300 mg/kg for single & 37.5 to 600 mg/kg/8 h for multiple oral dosing).

A cell-permeable, orally bioavailable, nontoxic, nonsteroidal naphthylmethylimidazole compound that as a potent, selective and reversible inhibitor of 17,20-lyase (IC₅₀ = 140 nM, 27 nM, and 1.2 µM in human, monkey, and rat, respectively) and reduces the weight of androgen-dependent organs. At higher concentrations, affects 17α-hydroxylase (IC₅₀ = 760, 38 and >10,000 nM in human, monkey and rat, respectively) activity with minimal effect on 11β-hydroxylase. Suppresses testosterone (IC₅₀ = 640 nM) and androstenedione (IC₅₀ = 210 nM) production without affecting the synthesis of corticosterone or aldosterone in rats (up to 30 µM). Displays desirable pharmacokinetic properties (t_1/2 - 3.8 h; T_max = 1.7 h; AUC = 0.727 mg h/ml following an oral dose of 1 mg/kg in monkey).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

Cell permeable: yes

Primary Target
17,20-lyase

Reversible: yes

Secondary Target
17α-hydroxylase

Packaged under inert gas

Dreicer, R., et al. 2014. Clin. Cancer Res.20, 1335.
Yin, L. and Hu, Q., 2014. Nat. Rev. Urol.11, 32.
Hara, T., et al. 2013.J. Steroid Biochem. Mol. Biol.134, 80.
Yamaoka, M., et al. 2012. J. Steroid Biochem. Mol. Biol.129, 115.
Kaku, T., et al. 2011. Bioorg. Med. Chem.19, 6383.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)