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Purity: ≥98%
AB-423, a member of the sulfamoylbenzamide (SBA) class, is a potent HBV (hepatitis B virus) capsid assembly inhibitor that inhibits HBV replication with EC50/EC90 of 0.08-0.27 μM/0.33-1.32 μM in cells. AB-423 is currently under phase 1 clinical trials. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein.
| Targets |
HBV capsid
Hepatitis B Virus (HBV) core protein dimer-dimer interface (EC₅₀ = 0.08–0.27 μM; EC₉₀ = 0.33–1.32 μM) [1] |
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| ln Vitro |
Anti-HBV capsid assembly inhibitor AB-423. With EC50s of approximately 0.260 μM, AB-423 inhibits the production of rcDNA in AML12-HBV10 and HepDE19 cells. Additionally, AB-423 inhibits HBV DNA levels in culture supernatants of HepG 2.2.15 cells with an EC50 of 0.134 μM and suppresses cccDNA formation-dependent HBeAg production in the HepBHAe82 assay with an EC50 of 0.267 μM. Nonetheless, none of the three cell lines exhibit any cytotoxicity from AB-423[1].
AB-423 potently inhibits HBV replication in cell culture models, with EC₅₀ ranging from 0.08 to 0.27 μM and EC₉₀ from 0.33 to 1.32 μM; no significant cytotoxicity is observed (50% cytotoxic concentration > 10 μM) [1] Addition of 40% human serum increases the EC₅₀ of AB-423 by 5-fold [1] AB-423 effectively inhibits HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro [1] Treatment of HepDES19 cells with AB-423 (3 μM) for 6 days results in capsid particles lacking encapsidated pregenomic RNA (pgRNA) and relaxed circular DNA (rcDNA), confirming it as a class II capsid inhibitor [1] In C3Aᵏᴺᵀᶜᴾ cells (de novo infection model), AB-423 (3 μM) inhibits the conversion of encapsidated rcDNA to covalently closed circular DNA (cccDNA) when treatment starts 24 h preinfection and continues to day 6 postinfection; cccDNA copy number and pgRNA levels are reduced compared to DMSO-treated samples [1] AB-423 modulates HBV capsid assembly in a biochemical assay, showing dose-dependent activity in an 8-point dilution series (starting from 30 μM, 1/2-log serial dilution) with triplicate samples [1] Dual combination studies in vitro show additive to synergistic antiviral activity between AB-423 and anti-HBV agents (nucleos(t)ide analogs: entecavir, tenofovir disoproxil fumarate; RNA interference agents: ARB-1467, ARB-1740; interferon alpha) in various cell assays (AML12-HBV10, HepDES19, HepBHAe82 cells) [1] |
| ln Vivo |
In a mouse model of HBV, AB-423 (30 and 100 mg/kg, p.o. bid) inhibits HBV replication. In an HDI model of HBV in immunodeficient NOD-SCID mice, AB-423 (100 mg/kg, p.o. bid) combined with entecavir (ETV, 100 ng/mg, qd, p.o.) or 0.1 mg/kg dose of ARB-1467 potently inhibits serum HBV DNA[1].
In CD-1 mice, AB-423 shows significant systemic exposures and higher accumulation levels in the liver after single intravenous (i.v.) or oral (p.o.) administration [1] In a hydrodynamic injection (HDI) mouse model of HBV infection, twice-daily administration of AB-423 for 7 days induces a dose-dependent reduction in serum HBV DNA levels [1] Combination of AB-423 with entecavir or ARB-1467 in the HDI mouse model shows a trend toward greater antiviral activity than either agent alone, consistent with in vitro combination results [1] |
| Enzyme Assay |
Perform molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and sulfamoylbenzamides (SBAs) to predict its binding mode to the HBV core protein dimer-dimer interface [1]
Conduct a biochemical HBV capsid assembly assay with AB-423 tested in an 8-point dose range (starting at 30 μM, 1/2-log serial dilution) in triplicate; measure capsid assembly modulation to assess dose-response activity [1] |
| Cell Assay |
HepBHAe82 (50,000 cells/well) are plated in 96-well tissue-culture treated microtiter plates in DMEM/F12 medium supplemented with 1% penicillin-streptomycin, 1% fetal bovine serum, and 1% tetracycline (1 μg/mL). The cells are then incubated for an entire night at 37°C and 5% CO2 in a humidified incubator. This is done to test the compound combinations. The cells are treated with inhibitors A and B the following day, with concentration ranges close to their individual EC50 values, after being transferred to a fresh medium.The inhibitors are diluted in either growth medium (ARB-1467 and ARB-1740) or 100% DMSO (ETV, TDF, and AB-423). The assay's final DMSO concentration is ≤0.5%. The effects of the two inhibitors on the inhibition of rcDNA production are assessed both individually and in combination. In the assay, the final DMSO concentration is 0.5%. The plates are kept in a humidified incubator with 5% CO2 and 37°C for nine days. After incubating for nine days, the medium is removed, and the cells undergo RNA extraction in order to quantify the precore mRNA level that is dependent on cccDNA[1].
Treat HepDES19 cells with AB-423 (3 μM), DMSO (vehicle), GLS-4, or 3TC for 6 days; extract and analyze intracellular viral RNA (Northern blotting with HBV-specific ³²P-labeled riboprobe), encapsidated pgRNA (Northern blotting), intracellular HBV core protein (Western blotting), total nucleocapsids (particle gel assay), and HBV DNA replication intermediates (rcDNA, ssDNA; Southern blotting); use 18S and 28S rRNAs as loading controls [1] Treat C3Aᵏᴺᵀᶜᴾ cells with AB-423 (3 μM), DMSO, myrcludex B (100 nM), or IFN-α (1000 IU/ml) starting 24 h preinfection and continuing to day 6 postinfection; harvest cells and quantify cccDNA (qPCR) and pgRNA (quantitative RT-PCR) [1] Perform in vitro combination assays by treating AML12-HBV10, HepDES19, or HepBHAe82 cells with AB-423 combined with nucleos(t)ide analogs, RNAi agents, or IFN-α; use checkerboard synergy plots (MacSynergy II analysis) and antiviral dose-response curves to evaluate additive/synergistic effects with quadruplicate samples [1] |
| Animal Protocol |
Mice
NOD receives 10 micrograms of the plasmid pHBV1.3 prior to the start of treatment.hydrodynamic injection (HDI; fast, high-volume injection into the tail vein; n = 6–8 animals per group) of CB17-Prkdcscid/J mice. Hepatitis B virus particles and other HBV products are produced when the 1.3-fold overlength copy of the HBV genotype D genome contained in this plasmid is expressed. Beginning on Day 0, AB-423 is given orally twice a day for seven days at a dose of 30 or 100 mg/kg. Beginning on Day 0, entecavir (ETV) at 100 ng/kg once daily for seven days in a row. On Day 0, a single intravenous bolus tail vein injection of ARB-1467 at a dose of 0.1 mg/kg is given. Days 0 (pre-dose), 4, and 7 are when blood is drawn for HBV biomarker analysis. Through the use of primer/probe sequences in a quantitative PCR assay, the amount of HBV DNA present in mouse serum is determined from the total extracted DNA[1]. Conduct pharmacokinetic studies in CD-1 mice by administering a single i.v. or p.o. dose of AB-423; collect plasma samples at different time points to measure drug concentrations (mean ± SD, n=3 per group) [1] Establish the HDI mouse model of HBV infection; administer AB-423 twice daily via oral gavage for 7 days (starting on day 0) at different doses; measure serum HBV DNA levels to assess dose-dependent antiviral activity (n=5–6 per group) [1] For combination studies in the HDI mouse model: administer AB-423 twice daily via oral gavage for 7 days, entecavir once daily via oral gavage for 7 days (both starting on day 0), or ARB-1467 as a single i.v. bolus tail vein injection on day 0; measure serum HBV DNA and HBsAg levels relative to predose (day 0) values (n=4–8 per group) [1] |
| ADME/Pharmacokinetics |
AB-423 showed significant systemic exposure in CD-1 mice after a single intravenous or oral administration [1]. AB-423 accumulated at higher levels in the liver of CD-1 mice than in the systemic circulation [1].
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| Toxicity/Toxicokinetics |
AB-423 showed no significant cytotoxicity in vitro, with a 50% cytotoxicity concentration greater than 10 μM [1]
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| References | |
| Additional Infomation |
AB-423 belongs to the sulfonylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors, and its chemical structure is (R)-5-[N-(sec-butyl)sulfonyl]-N-(3,4-difluorophenyl)-2-fluorobenzamide[1]. As a class II capsid inhibitor, it interferes with the packaging and uncoating of HBV pgRNA, preventing the formation of functional capsids and the conversion of rcDNA to cccDNA[1]. Biochemical studies and molecular docking have shown that AB-423 binds to the dimer-dimer interface of HBV core protein[1]. AB-423 is currently in the Phase I clinical trial stage for the treatment of chronic hepatitis B, and its preclinical study results support further evaluation of its safety, pharmacokinetics and antiviral activity in patients[1].
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| Molecular Formula |
C17H17F3N2O3S
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| Molecular Weight |
386.39
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| Exact Mass |
386.09
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| Elemental Analysis |
C, 52.84; H, 4.43; F, 14.75; N, 7.25; O, 12.42; S, 8.30
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| CAS # |
1572510-80-5
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| Related CAS # |
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| PubChem CID |
90259477
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| Appearance |
White to off-white solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
584
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC[C@@H](C)NS(=O)(=O)C1=CC(=C(C=C1)F)C(=O)NC2=CC(=C(C=C2)F)F
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| InChi Key |
BBLXLHYPDOMJMO-SNVBAGLBSA-N
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| InChi Code |
InChI=1S/C17H17F3N2O3S/c1-3-10(2)22-26(24,25)12-5-7-14(18)13(9-12)17(23)21-11-4-6-15(19)16(20)8-11/h4-10,22H,3H2,1-2H3,(H,21,23)/t10-/m1/s1
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| Chemical Name |
(R)-5-(N-(sec-Butyl)sulfamoyl)-N-(3,4-difluorophenyl)-2-fluorobenzamide
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| Synonyms |
AB-423; AB 423; AB423
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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 |
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| 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 : 77~100 mg/mL ( 199.28~258.81 mM )
Ethanol : ~77 mg/mL Water : ˂1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.47 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 25.0 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: ≥ 2.5 mg/mL (6.47 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 10% DMSO+90% Corn Oil: ≥ 2.5 mg/mL (6.47 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5881 mL | 12.9403 mL | 25.8806 mL | |
| 5 mM | 0.5176 mL | 2.5881 mL | 5.1761 mL | |
| 10 mM | 0.2588 mL | 1.2940 mL | 2.5881 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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