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| Targets |
Seviteronel racemate targets CYP17A1 (cytochrome P450 17A1), a key enzyme in steroidogenesis that catalyzes both 17alpha-hydroxylase and 17,20-lyase activities. CYP17A1 is essential for the production of androgens and estrogens from cholesterol precursors. By inhibiting CYP17 lyase activity, Seviteronel reduces androgen synthesis without inducing mineralocorticoid excess or cortisol depletion. The racemate form contains both enantiomers and is used as a reference standard or for comparative studies. Seviteronel has potential anti-androgenic and antineoplastic activities and has been investigated for the treatment of castration-resistant prostate cancer.
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| ln Vitro |
Seviteronel (VT-464) is a nonsteroidal small chemical that suppresses androgen synthesis by selectively inhibiting CYP17 17,20-lyase without inducing mineralocorticoid excess or cortisol depletion. We investigated the effects of Seviteronel on tumor growth in the mCRPC xenograft MDA-PCa-133 in vivo and androgen signaling in C4-2B prostate cancer cells in vitro [2].
In vitro activity of Seviteronel racemate is expected to reflect the combined activity of both enantiomers. Seviteronel is a potent CYP17 lyase inhibitor. The compound specifically targets cytochrome P450 17A1, a crucial enzyme in steroidogenesis. Seviteronel inhibits androgen production without inducing mineralocorticoid excess or cortisol depletion by selective inhibition of CYP17 17,20-lyase. The racemate is used in research focused on hormone-dependent cancers. Comprehensive in vitro activity data for the racemate specifically are available from research publications. |
| ln Vivo |
Clinical CRPC bone metastases were used to create MDA-PCa-133 xenografts. The expression of PSA, full-length androgen receptor (AR), and the AR-V7 isoform is observed in subcutaneous MDA-PCa-133 tumors. In castrated male tumor-bearing mice, we examined the effects of AA and Seviteronel (VT-464) on the growth of MDA-PCa-133. The mice were randomly assigned to three groups and given oral vehicle alone, 100 mg/kg bid of Seviteronel (VT-464), or 100 mg/kg bid of AA for a 25-day period. Tumor volume was decreased by both AA and seviteronel (VT-464) (>2fold relative to vehicle; p<0.05). In this model, these findings suggest that AA CYP17 inhibition is not as effective as selective Seviteronel (VT-464) CYP17 lyase inhibition [2].
In vivo activity of Seviteronel racemate has been studied in preclinical models. Seviteronel is an orally bioavailable, non-steroidal, lyase-selective CYP17 inhibitor with potential anti-androgenic and antineoplastic activities. Seviteronel has been investigated for the treatment of castration-resistant prostate cancer and other hormone-dependent cancers. The racemate is used as a research tool to study the pharmacological activity of Seviteronel. Comprehensive in vivo efficacy data for Seviteronel have been reported in research publications. The compound's oral bioavailability makes it suitable for convenient dosing in research settings. |
| Enzyme Assay |
In vitro enzyme assays for Seviteronel racemate involve measuring the inhibition of CYP17 lyase activity. CYP17A1 enzyme is incubated with varying concentrations of the test compound and the substrate (e.g., progesterone or pregnenolone). The conversion of the substrate to androgen precursors is quantified by HPLC or LC-MS/MS. IC50 values are calculated by plotting percent inhibition against compound concentration using non-linear regression analysis. Selectivity assays compare the compound's activity against other cytochrome P450 enzymes involved in steroidogenesis. Each concentration is typically tested in duplicate or triplicate with appropriate positive controls (known CYP17 inhibitors) and vehicle controls. The racemate's IC50 for CYP17 lyase inhibition is in the nanomolar range.
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| Cell Assay |
In vitro cellular assays for Seviteronel racemate are performed using hormone-dependent cancer cell lines such as LNCaP or VCaP prostate cancer cells. Cells are treated with varying concentrations of the compound for defined time periods. Androgen production and cell proliferation are measured. Testosterone and dihydrotestosterone (DHT) levels in the culture medium are measured by ELISA or LC-MS/MS. Cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. Apoptosis is measured using annexin V/propidium iodide staining or caspase activity assays. Androgen receptor signaling is assessed by measuring PSA expression or androgen receptor target gene expression by qRT-PCR. Cytotoxicity is assessed in parallel to ensure that observed effects are not due to cell death. IC50 values for inhibition of cell proliferation are calculated from dose-response curves.
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| Animal Protocol |
In vivo animal studies for Seviteronel racemate are conducted using mouse xenograft models of prostate cancer. Immunodeficient mice are implanted subcutaneously with prostate cancer cells and treated with Seviteronel via oral gavage at various doses and schedules. Tumor growth is measured using calipers. Serum testosterone and other androgen levels are measured to confirm target engagement. Pharmacokinetic studies assess drug concentrations in plasma. Animals are monitored for clinical signs and body weight. Efficacy is expressed as tumor growth inhibition compared to vehicle-treated controls. Comprehensive in vivo efficacy data have been reported in research publications.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Seviteronel racemate have been characterized in preclinical studies. The compound has a molecular formula of C18H17F4N3O3 and a molecular weight of 399.34 g/mol. Its IUPAC name is 1-(6,7-bis(difluoromethoxy)naphthalen-2-yl)-2-methyl-1-(1H-1,2,3-triazol-4-yl)propan-1-ol. Seviteronel is orally bioavailable. Comprehensive pharmacokinetic parameters including half-life, volume of distribution, clearance, and oral bioavailability have been characterized in animal models. The compound's pharmacokinetic profile supports its use in preclinical studies of hormone-dependent cancers.
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| Toxicity/Toxicokinetics |
Seviteronel racemate is intended for laboratory research use only and has not undergone comprehensive clinical toxicology testing. As a CYP17 inhibitor that modulates steroidogenesis, the compound would be expected to have effects on hormone-dependent tissues. Standard in vitro cytotoxicity assays in cell lines are typically performed alongside efficacy studies to rule out nonspecific toxicity. In vivo, animals are monitored for signs of toxicity including body weight changes, behavioral abnormalities, and clinical observations. Comprehensive toxicological characterization including genotoxicity and repeated-dose toxicity studies has been conducted as part of preclinical development. The compound is not approved for human use and is strictly intended for research purposes.
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| References |
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| Additional Infomation |
Seviteronel racemate (VT-464 racemate) is the racemate form of Seviteronel (VT-464), a potent CYP17 lyase inhibitor. Seviteronel inhibits androgen production without mineralocorticoid excess or cortisol depletion by selective inhibition of CYP17 17,20-lyase. The compound has a molecular formula of C18H17F4N3O3 and a molecular weight of 399.34 g/mol. Seviteronel racemate has not entered clinical trials and has not received regulatory approval for any indication. It is available from research chemical suppliers for non-clinical research purposes only.
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| Molecular Formula |
C18H17F4N3O3
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| Molecular Weight |
399.339498281479
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| Exact Mass |
399.121
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| CAS # |
1375603-36-3
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| Related CAS # |
Seviteronel;1610537-15-9;Seviteronel (R enantiomer);1375603-38-5
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| PubChem CID |
69093450
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.052
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
28
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| Complexity |
517
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)C(C1=CC2=CC(=C(C=C2C=C1)OC(F)F)OC(F)F)(C3=NNN=C3)O
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| InChi Key |
ZBRAJOQFSNYJMF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H17F4N3O3/c1-9(2)18(26,15-8-23-25-24-15)12-4-3-10-6-13(27-16(19)20)14(28-17(21)22)7-11(10)5-12/h3-9,16-17,26H,1-2H3,(H,23,24,25)
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| Chemical Name |
1-[6,7-bis(difluoromethoxy)naphthalen-2-yl]-2-methyl-1-(2H-triazol-4-yl)propan-1-ol
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~125.21 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (7.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (7.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5041 mL | 12.5207 mL | 25.0413 mL | |
| 5 mM | 0.5008 mL | 2.5041 mL | 5.0083 mL | |
| 10 mM | 0.2504 mL | 1.2521 mL | 2.5041 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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