TAK-700 (Orteronel)

Catalog No.S1195

TAK-700 (Orteronel) is a potent and highly selective human 17,20-lyase inhibitor with IC50 of 38 nM, exhibits >1000-fold selectivity over other CYPs (e.g. 11-hydroxylase and CYP3A4). Phase 3.

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TAK-700 (Orteronel) Chemical Structure

TAK-700 (Orteronel) Chemical Structure
Molecular Weight: 307.35

Validation & Quality Control

Quality Control & MSDS

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TAK-700 (Orteronel) is available in the following compound libraries:

Product Information

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Product Description

Biological Activity

Description TAK-700 (Orteronel) is a potent and highly selective human 17,20-lyase inhibitor with IC50 of 38 nM, exhibits >1000-fold selectivity over other CYPs (e.g. 11-hydroxylase and CYP3A4). Phase 3.
Targets 17,20-lyase (Human) [1] 17,20-lyase (Rat) [1]
IC50 38 nM 54 nM
In vitro 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]
In vivo 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]
Features

Protocol(Only for Reference)

Kinase Assay: [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.

Animal Study: [1]

Animal Models Adult male cynomolgus monkeys.
Formulation TAK-700 is dissolved in 0.5% methylcellulose.
Dosages ≤1 mg/kg
Administration Administered via p.o.
Solubility 0.5% methylcellulose, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA

SpeciesWeight (kg)Body Surface Area (m2)Km factor
Baboon120.620
Dog100.520
Monkey30.2412
Rabbit1.80.1512
Guinea pig0.40.058
Rat0.150.0256
Hamster0.080.025
Mouse0.020.0073
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

Value based on data from FDA Draft Guidelines: Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. (2002) Estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers, U.S. Food and Drug Administration, Rockville, Maryland, USA.

For example, to convert the dose of resveratrol used in a mouse (22.4 mg/kg) to a dose based on surface area for rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[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.

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02101684 Recruiting Metastatic or Advanced Non-resectable Granulosa Cell Ovarian Tumors Grupo Español de Tumores Huérfanos e Infrecuentes|Takeda June 2014 Phase 2
NCT02053311 Not yet recruiting Prostate Cancer Swiss Group for Clinical Cancer Research June 2014 Phase 3
NCT02054793 Withdrawn Prostate Cancer|Castration-resistant Prostate Cancer Johns Hopkins University|Emmanuel Antonarakis, MD|Millennium Pharmaceuticals, Inc. June 2014 Phase 1|Phase 2
NCT01990209 Recruiting Metastatic Breast Cancer SCRI Development Innovations, LLC|Millennium Pharmaceuticals, Inc. February 2014 Phase 2
NCT01658527 Withdrawn Prostate Cancer European Organisation for Research and Treatment of Cancer - EORTC January 2014 Phase 2

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Chemical Information

Download TAK-700 (Orteronel) SDF
Molecular Weight (MW) 307.35
Formula

C18H17N3O2

CAS No. 426219-18-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 61 mg/mL (198 mM)
Water <1 mg/mL (<1 mM)
Ethanol 8 mg/mL (26 mM)
In vivo 0.5% methylcellulose, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (S)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-e]imidazol-7-yl)-N-methyl-2-naphthamide

Research Area

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