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Purity: ≥98%
JNJ-632 is a novel and potent hepatitis B virus (HBV) capsid assembly modulator (CAM). Small molecule induced hepatitis B virus (HBV) capsid assembly modulation is considered an attractive approach for new antiviral therapies against HBV. JNJ-632 has been used as a tool compound to further profile the mode of action. Administration of JNJ-632 (54) in HBV genotype D infected chimeric mice resulted in a 2.77 log reduction of the HBV DNA viral load.
| Targets |
HBV
HBV capsid assembly modulator (CAM), specifically a sulfamoylbenzamide derivative that accelerates HBV core protein aggregation, preventing encapsidation of pregenomic RNA (pgRNA) and viral polymerase, thereby inhibiting HBV DNA synthesis and virion production.[1] |
|---|---|
| ln Vitro |
Hepatitis B virus (HBV) inhibition is achieved by JNJ-632, a capsid assembly modulator. HBV DNA HepG2.2.15 and HBV DNA HepG2.117 are inhibited by JNJ-632, with EC50 values of 0.12 and 0.43 μM, respectively. Within the 10-30 μM range, which is regarded as weakly cytotoxic, JNJ-632 exhibits EC20s in the high-content multiparameter cytotoxicity (HepG2)[1].
Inhibition of HBV DNA replication in HepG2.2.15 cells (genotype D) with an EC₅₀ of 0.12 µM (Table 5). Inhibition of HBV DNA in HepG2.117 cells with an EC₅₀ of 0.43 µM (Table 5). Anti-HBV activity in HBV-infected primary human hepatocytes (PHHs) derived from naïve chimeric mice with an EC₅₀ of 200 nM for genotype D, similar to the activity in HepG2.2.15 cells.[1] |
| ln Vivo |
C57BL/6 mice are used to assess the single dose PK profile of JNJ-632 after both intravenous (IV) and oral (PO) administration. JNJ-632 exhibits a moderate volume of distribution of 1.3 L/kg and a moderate plasma clearance of 34 mL/min/kg.After oral administration of 10 mg/kg, the oral bioavailability is 40%, and after oral administration of 50 mg/kg, it is 66%. With t1/2s of 0.42±0.06 h, 1.1±0.67 h, 2.4±2.3 h, and 5.3±0.1 h for 2.5 mg/kg (iv), 10 mg/kg (po), 50 mg/kg (po), and 50 mg/kg (sc), JNJ-632 has a moderate terminal elimination half-life. JNJ-632 is also administered subcutaneously to C57BL/6 mice at a dose of 50 mg/kg in order to avoid the first pass metabolism. This causes a concentration of 102 ng/mL in plasma and 1297 ng/g in the liver 24 hours after dosing[1].
Subcutaneous administration of JNJ-632 (200 mg/kg, once daily for 28 days) in HBV genotype D-infected chimeric mice resulted in a mean reduction of serum HBV DNA by 2.77 log, demonstrating inhibition of HBV replication in vivo. No reduction in HBeAg or HBsAg levels was observed during the 28-day study.[1] |
| Cell Assay |
HBV DNA inhibition was measured in stable HepG2.2.15 and HepG2.117 cell lines after 4–6 days of compound treatment. Cytotoxicity was assessed in HepG2 cells using a high-content multiparameter cytotoxicity assay, showing an EC₂₀ in the 10–30 µM range, indicating weak cytotoxicity.[1]
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| Animal Protocol |
Mice [1]
Male C57BL/6 mice that have been fed are used to assess the pharmacokinetic profile (n=3/group). JNJ-632, formulated as a 0.5 mg/mL solution in PEG400/water (70/30), is administered intravenously (i.v.) to mice at a dose of 2.5 mg/kg. Blood is drawn from the saphenous vein at 0.05, 0.17, 0.5, 1, 2, 4, 7, and 24 hours and placed into microcentrifuge tubes containing EDTA. JNJ-632 is taken orally at 10 and 50 mg/kg; it is prepared as a 0.5 and 2.5 mg/mL suspension in methocel 0.5% w/v. Blood is drawn at 0.5, 1, 2, 4, 7, 9, and 24 hours from the saphenous vein and placed into microcentrifuge tubes containing EDTA. JNJ-632 is given subcutaneously at a dose of 50 mg/kg, and blood is drawn. The plasma was kept at -20°C while the blood samples were promptly centrifuged at 4°C[1]. JNJ-632 was administered subcutaneously once daily at 200 mg/kg for 28 days to HBV genotype D-infected chimeric mice with humanized livers. Saline (oral) and entecavir (ETV, 0.03 mg/kg oral) served as negative and positive controls, respectively. Serum HBV DNA levels were monitored by qPCR.[1] |
| ADME/Pharmacokinetics |
In C57BL/6 mice, JNJ-632 showed moderate plasma clearance (34 mL/min/kg), moderate volume of distribution (1.3 L/kg), and oral bioavailability of 40% at a dose of 10 mg/kg and 66% at a dose of 50 mg/kg. In C57BL/6 mice, plasma concentrations were 102 ng/mL and liver concentrations were 1297 ng/g 24 hours after subcutaneous injection (50 mg/kg). In uninfected humanized mice, drug exposure was higher on day 8 after repeated subcutaneous injection (50 and 200 mg/kg) than on day 1. In human liver microsomes (HLM), the turnover rate of JNJ-632 after 15 minutes was 26%; in mouse liver microsomes (MLM), the turnover rate after 15 minutes was 51%. [1]
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| Toxicity/Toxicokinetics |
In a high-throughput, multi-parameter cytotoxicity assay conducted in HepG2 cells, the EC₂₀ value of JNJ-632 was in the range of 10–30 µM, indicating that it had weak cytotoxicity. In chimeric mice, no decrease in human serum albumin levels was observed after 28 days of treatment, suggesting that it had no cytotoxic effect on human hepatocytes. [1]
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| References | |
| Additional Infomation |
JNJ-632 is a tool compound derived from the optimization of a lead compound of an N-phenyl-3-aminosulfonylbenzamide derivative. It acts as a capsid assembly regulator (CAM) to inhibit HBV replication in vitro and in vivo. Molecular docking studies have shown that it binds to the hydrophobic pocket of the HBV core protein, binds to Trp102 and Thr128 via hydrogen bonds, and interacts with Leu140 via a sulfonamide group. [1]
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| Molecular Formula |
C18H19FN2O4S
|
|---|---|
| Molecular Weight |
378.417866945267
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| Exact Mass |
378.11
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| Elemental Analysis |
C, 57.13; H, 5.06; F, 5.02; N, 7.40; O, 16.91; S, 8.47
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| CAS # |
1572510-42-9
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| PubChem CID |
73389570
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| Appearance |
White to off-white solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
595
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(C=CC(=C1)NC(=O)C2=CC(=CC=C2)S(=O)(=O)N[C@H]3CCOC3)F
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| InChi Key |
JIZGLOVJKCSHTH-HNNXBMFYSA-N
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| InChi Code |
InChI=1S/C18H19FN2O4S/c1-12-9-14(5-6-17(12)19)20-18(22)13-3-2-4-16(10-13)26(23,24)21-15-7-8-25-11-15/h2-6,9-10,15,21H,7-8,11H2,1H3,(H,20,22)/t15-/m0/s1
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| Chemical Name |
(S)-N-(4-fluoro-3-methylphenyl)-3-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide
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| Synonyms |
JNJ 632; JNJ632;JNJ-632
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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 : 76~125 mg/mL ( 200.83~330.32 mM )
Ethanol : ~76 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.50 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 (5.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (5.50 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 (5.50 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6426 mL | 13.2128 mL | 26.4257 mL | |
| 5 mM | 0.5285 mL | 2.6426 mL | 5.2851 mL | |
| 10 mM | 0.2643 mL | 1.3213 mL | 2.6426 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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