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生物活性
产品描述
TAK-700 (Orteronel)是一种有效的，高度选择性的，人17，20-lyase抑制剂，IC50为38 nM，比作用于其他CYPs(例如11-羟化酶和CYP3A4)选择性高1000倍以上。Phase 3。
靶点
17,20-lyase (Rat)
17,20-lyase (Human)
 
 
 
 
IC50
54 nM [1]
38 nM [1]
 
 
 
 
体外研究
In vitro, TAK-700 shows the potent inhibitory activity against rat and human steroid 17,20-lyase inhibitor with IC50 of 54 nM and 38 nM, respectively. While other CYP isoforms including 11-hydroxylase and CYP3A4 are not significantly affected by TAK-700. [1] In microsomes expressing human CYP isoforms, TAK-700 exhibit greater inhibitory effects on 17,20-lyase with IC50 of 19 nM compared to the other CYP isoforms. [1] TAK-700 shows the inhibitory activity against monkey 17,20-lyase and 17-hydroxylase with IC50 of 27 nM and 38 nM, respectively. [2] In monkey adrenal cells, TAK-700 inhibits the ACTH stimulated production of DHEA and androstenedione with IC50 of 110 nM and 130 nM, respectively. Moreover, TAK-700 also potently inhibits DHEA production in human adrenocortical tumor line H295R cells with IC50 of 37 nM. [2]
体内研究
In cynomolgus monkeys, oral treatment of TAK-700 at a dose of 1 mg/kg markedly reduces serum testosterone and dehydroepiandrosterone (DHEA) levels. [1] Oral treatment of TAK-700 at a dose of 1 mg/kg results in favorable pharmacokinetic parameters with Tmax, Cmax, t1/2 and AUC0-24 hours of 1.7 hours, 0.147 μg/mL, 3.8 hours and 0.727 μg h/mL, respectively. [2]
特征
 
推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)
激酶实验: [1]
Inhibitory activity on steroid 17,20-lyase in vitro
Testes excised from 13-week-old male SD rats are homogenized, and testicular microsomes are prepared by centrifugation. The reaction mixture contained 75 mM phosphate buffer (pH 7.4), 7 μg of the microsome protein, 10 nM [1,2-3H]-17α-hydroxyprogesterone (NEN), 5 mM NADPH (Oriental Yeast), and 1 nM-1000 nM TAK-700 in a total volume of 20 μL at room temperature. The concentration of reagents is expressed as the final concentration in the reaction mixture. TAK-700 is serially diluted with dimethylformamide, and then diluted fivefold with distilled water before 5 μL of the diluted solution is added to the reaction mixture. After incubating for 15 minutes at 37 °C the reaction is terminated by the addition of 40 μL of ethyl acetate, then vortexed for 30 seconds and briefly centrifuged. Thirty microliters of the organic phases are applied to silica gel TLC plates. The substrate and the products, androstenedione and testosterone, are separated using the toluene-acetone (7:2) solvent system. Detection of the spots and measurement of the radioactivity as PSL are performed with a BAS2000 Bio-image analyzer (FUJIX). The concentration of TAK-700 needed to reduce the concentration of the products by 50% (the concentration of the control group in which no TAK-700 is added is taken as 100%) is calculated. Inhibitory activity on human enzymes is determined as described above. The reaction mixture contained 75 mM phosphate buffer (pH 7.4), 1 mM magnesium chloride, 0.5 pmol of recombinant P450c17, 0.5 pmol of recombinant cytochrome b5, 20.8 ng of recombinant NADPH-cytochrome P450 reductase, 10 nM [1,2-3H]-17α-hydroxypregnenolone, 5 mM NADPH (Oriental Yeast), and 1 nM-1000 nM test compound in a total volume of 20 μL. The concentration of reagents is expressed as the final concentration in the reaction mixture. TAK-700 is serially diluted with dimethylformamide, and then diluted fivefold with distilled water before 5 μL of the diluted solution is added to the reaction mixture. After incubating for 15 minutes incubation at 37 °C the reaction is terminated by the addition of 40 μL of ethyl acetate, then vortexed for 30 seconds and briefly centrifuged. Thirty microliters of the organic phases are applied to silica gel TLC plates. The substrate and the product DHEA are separated using the cyclohexane-ethyl acetate (3:2) solvent system.
动物实验: [1]
动物模型
Adult male cynomolgus monkeys.
配制
TAK-700 is dissolved in 0.5% methylcellulose.
剂量
≤1 mg/kg
给药处理
Administered via p.o.
溶解度
0.5% methylcellulose, 30 mg/mL
参考文献
[1] Kaku T, et al. Bioorg Med Chem. 2011, 19(21), 6383-6399.
[2] Yamaoka M, et al. J Steroid Biochem Mol Biol. 2012, 129(3-5), 115-128.