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| 25mg |
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| Targets |
NVR 3-778 targets the hepatitis B virus (HBV) capsid assembly process. It is a capsid assembly modulator, meaning it interferes with the formation of the viral capsid, a protein shell that encases the viral genetic material. By disrupting this essential step in the viral life cycle, it prevents the generation of infectious HBV DNA-containing virus particles. This mechanism is distinct from that of nucleos(t)ide inhibitors, and it shows no cross-resistance with them.
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| ln Vitro |
Viral replication is inhibited by NVR 3-778, which targets the HBV core protein [1]. NVR 3-778 has an average antiviral effect EC50 of 0.40 µM in HepG2.2.15 cells, which means that it can prevent the generation of viral particles containing infectious HBV DNA [1]. Nucleos(t)ide inhibitors of HBV replication do not cause cross-resistance when used with NVR 3-778, which demonstrates genotype-wide antiviral efficacy [1]. NVR 3-778 prevents the generation of particles containing HBV DNA and HBV RNA, viral replication, and pregenomic RNA encapsidation [1]. With an EC50 of 0.81 µM against HBV DNA and 3.7 to 4.8 µM against HBV antigen and intracellular HBV RNA, NVR 3-778 also prevents de novo infection and viral replication in primary human hepatocytes [1]. When 10%, 20%, and 40% human serum were present, the EC50 values of NVR 3-778 rose by 4.5, 9.3, and 15.8 times, respectively [1].
In vitro, NVR 3-778 exhibits potent antiviral activity against HBV. It inhibits the generation of infectious HBV DNA-containing virus particles with a mean EC50 of 0.40 µM in HepG2.2.15 cells. It achieves this by inhibiting pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and RNA-containing particles. Its pan-genotypic antiviral activity is a key feature of its in vitro profile. |
| ln Vivo |
Following oral delivery to dogs, NVR 3-778 (1.5 mg/kg; ig) demonstrated mean Cmax and AUC0–inf values of 0.56 µg/ml and 3.50 µg·h/ml, respectively. It was found that the average oral bioavailability was 84.6% [1].
In vivo, NVR 3-778 has demonstrated antiviral activity in preclinical models. As an orally bioavailable compound, it can be administered to animals to study its effects on HBV replication. Its ability to inhibit HBV capsid assembly and viral replication supports its potential as a therapeutic agent for chronic hepatitis B. It has also advanced into clinical evaluation, indicating promising in vivo activity and safety. |
| Enzyme Assay |
In vitro enzyme/receptor binding studies are not applicable to NVR 3-778, as it is a capsid assembly modulator, not an enzyme inhibitor. Its activity is assessed in cell-based antiviral assays. In these assays, HBV-infected cells (e.g., HepG2.2.15) are treated with the compound, and the production of viral DNA and RNA is measured. This confirms its ability to inhibit viral replication.
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| Cell Assay |
In vitro cellular assays for NVR 3-778 are the primary method for evaluating its antiviral activity. In these experiments, cells (e.g., HepG2.2.15) are infected with HBV or contain stably replicating HBV. They are then treated with varying concentrations of the compound. The key readout is the inhibition of viral replication, measured by quantifying HBV DNA and RNA levels in the culture supernatant or cell lysate. The EC50 of 0.40 µM is determined from these assays.
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| Animal Protocol |
Animal/Disease Models: Dog [1]
Doses: 1.5 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: po (oral gavage) Experimental Results: Mean Cmax and AUC0–inf values were 0.56 µg/ml and 3.50 µg·h/ml, oral Bioavailability is 84.6%. In vivo animal studies for NVR 3-778 are conducted in preclinical models of HBV infection. While specific animal models are not detailed in the provided sources, these studies would involve administering the compound to animals (e.g., humanized liver chimeric mice) infected with HBV. Endpoints would include the reduction of serum and liver HBV DNA levels, as well as the assessment of liver histopathology. These studies support its clinical development. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of NVR 3-778 are characterized by its oral bioavailability. It has a molecular weight of 432.38 g/mol and a molecular formula of C₁₈H₁₆F₄N₂O₄S. These properties are favorable for an orally administered drug. Its development as a clinical candidate indicates that it has a suitable ADME profile for further investigation.
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| Toxicity/Toxicokinetics |
Toxicological data for NVR 3-778 are not extensively detailed in the provided sources. As an investigational antiviral agent, its safety profile has been evaluated in preclinical studies. While specific toxicity data are not available, its advancement into clinical evaluation suggests an acceptable safety and tolerability profile. Comprehensive safety data would be available from clinical trial reports.
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| References | |
| Additional Infomation |
NVR 3-778 is an investigational antiviral agent targeting HBV replication. Its CAS number is 1445790-55-5. It is a first-in-class capsid assembly modulator that has shown promise in preclinical models and has been evaluated in clinical trials. It represents a novel approach to treating chronic hepatitis B, with a mechanism distinct from existing nucleos(t)ide analogs.
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| Molecular Formula |
C18H16F4N2O4S
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| Molecular Weight |
432.38925743103
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| Exact Mass |
432.076
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| Elemental Analysis |
C, 50.00; H, 3.73; F, 17.58; N, 6.48; O, 14.80; S, 7.41
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| CAS # |
1445790-55-5
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| Related CAS # |
2093094-04-1 (hydrate);1445790-55-5 (free);
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| PubChem CID |
89663273
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.606
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| LogP |
3.13
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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 |
4
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| Heavy Atom Count |
29
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| Complexity |
672
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1C(=CC=C(C(NC2C=C(C(=C(C=2)F)F)F)=O)C=1)F)(N1CCC(CC1)O)(=O)=O
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| InChi Key |
KKMFSVNFPUPGCA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H16F4N2O4S/c19-13-2-1-10(18(26)23-11-8-14(20)17(22)15(21)9-11)7-16(13)29(27,28)24-5-3-12(25)4-6-24/h1-2,7-9,12,25H,3-6H2,(H,23,26)
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| Chemical Name |
4-Fluoro-3-((4-hydroxypiperidin-1-yl)sulfonyl)-N-(3,4,5-trifluorophenyl)benzamide
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| Synonyms |
NVR 3 778; NVR3 778; NVR-3-778; K-89; K 89; K89; NVR3778; NVR 3778; NVR-3778
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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 : 98 ~250 mg/mL (226.64 ~578.18 mM)
Ethanol : ~98 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.81 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 20.8 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: 2.08 mg/mL (4.81 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (4.81 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3127 mL | 11.5636 mL | 23.1273 mL | |
| 5 mM | 0.4625 mL | 2.3127 mL | 4.6255 mL | |
| 10 mM | 0.2313 mL | 1.1564 mL | 2.3127 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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