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426219-18-3 molecular structure
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6-{7-hydroxy-5H,6H,7H-pyrrolo[1,2-c]imidazol-7-yl}-N-methylnaphthalene-2-carboxamide

ChemBase ID: 73136
Molecular Formular: C18H17N3O2
Molecular Mass: 307.34648
Monoisotopic Mass: 307.1320768
SMILES and InChIs

SMILES:
c1c(cc2c(c1)cc(cc2)C1(c2n(CC1)cnc2)O)C(=O)NC
Canonical SMILES:
CNC(=O)c1ccc2c(c1)ccc(c2)C1(O)CCn2c1cnc2
InChI:
InChI=1S/C18H17N3O2/c1-19-17(22)14-3-2-13-9-15(5-4-12(13)8-14)18(23)6-7-21-11-20-10-16(18)21/h2-5,8-11,23H,6-7H2,1H3,(H,19,22)
InChIKey:
OZPFIJIOIVJZMN-UHFFFAOYSA-N

Cite this record

CBID:73136 http://www.chembase.cn/molecule-73136.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
6-{7-hydroxy-5H,6H,7H-pyrrolo[1,2-c]imidazol-7-yl}-N-methylnaphthalene-2-carboxamide
IUPAC Traditional name
orteronel
Synonyms
TAK700
TAK-700
CAS Number
426219-18-3
PubChem SID
162038056
PubChem CID
9883029

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1195 external link Add to cart Please log in.
Data Source Data ID
PubChem 9883029 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 12.853757  H Acceptors
H Donor LogD (pH = 5.5) 0.33183518 
LogD (pH = 7.4) 0.732847  Log P 0.7526204 
Molar Refractivity 88.298 cm3 Polarizability 34.23546 Å3
Polar Surface Area 67.15 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
17 expand Show data source
20 lyase expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1195 external link
Research Area
Description Cancer
Biological Activity
Description TAK-700 (Orteronel) is a potent and highly selective rat and human 17,20-lyase inhibitor with IC50 of 54 nM and 38 nM, respectively.
Targets Rat 17,20-lyase Human 17,20-lyase
IC50 54 nM [1] 38 nM [1]
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]
Clinical Trials TAK-700 is currently in Phase II clinical trials in patients with Nonmetastatic Castration-resistant Prostate Cancer (CRPC) and a Rising Prostate-specific Antigen (PSA).
Features
Combination Therapy
Description TAK-700 in combination with Docetaxel and Prednisone is currently in Phase I/II clinical trials in patients with Metastatic Castration-Resistant Prostate Cancer.
Protocol
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.
Doses ≤1 mg/kg
Administration Administered via p.o.
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.

REFERENCES

REFERENCES

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PATENTS

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