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Purity: ≥98%
Bay 41-4109 S-isomer is the less active enantiomer of Bay 41-4109. It shows less activity than Bay 41-4109. BAY 41-4109 is a novel and potent inhibitor of human hepatitis B virus (HBV) with an IC50 of 53 nM. BAY-41-4109 is a heteroaryldihydropyrimidine (HAP) antiviral compound effective on Hepatitis B virus (HBV) capsid assembly and on preformed HBV capsids.
| Targets |
Mice: For this study, HBV-transgenic mice are employed. The compounds (BAY 41-4109) are given to mice twice a day for 28 days in a suspension solution formulated with 0.5% tylose. The placebo is the 0.5% tylose. The animals are killed six hours after the last treatment, and the livers are taken out and frozen right away for further examination. The anesthetized animals' hearts are punctured to obtain blood[1].
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| ln Vitro |
Mice: For this study, HBV-transgenic mice are employed. The compounds (BAY 41-4109) are given to mice twice a day for 28 days in a suspension solution formulated with 0.5% tylose. The placebo is the 0.5% tylose. The animals are killed six hours after the last treatment, and the livers are taken out and frozen right away for further examination. The anesthetized animals' hearts are punctured to obtain blood[1].
In HepG2.2.15 cells, the inhibitory concentration 50 (IC50) of BAY 41-4109 against HBV replication was estimated to be 53 nM. The cytotoxic concentration 50 (CC50) for HepG2.2.15 cells was 7 µM. [1] The compound was identified from a class of heteroaryl-pyrimidines as a potent inhibitor of human hepatitis B virus (HBV) replication based on cell-based assays. [1] |
| ln Vivo |
Viral DNA in liver and plasma is dose-dependently reduced by BAY 41-4109, with an efficacy that is similar to that of 3TC. HBV transgenic mice's livers had lower levels of the hepatitis B virus core antigen (HBcAg) when BAY 41 -4109 is added. According to pharmacokinetic studies conducted on mice, rats and dogs exhibit fast absorption, with dose-proportional plasma concentrations of about 60% and a bioavailability of 30% [1]. By focusing on the viral capsid, BAY41-4109 prevents the growth of viruses in vivo [2].
In HBV-transgenic mice (Tg [HBV1.3 fsX−3′5′]), oral administration of BAY 41-4109 at doses of 15 and 30 mg/kg twice daily for 28 days significantly reduced HBV-specific DNA in the liver and plasma in a dose-dependent manner. The antiviral effect was more pronounced in plasma than in liver. Its efficacy in reducing hepatic viral DNA was comparable to or greater than that of 3TC (lamivudine) at the tested doses. [1] Immunohistological analysis of liver sections from transgenic mice treated with BAY 41-4109 (30 mg/kg, three times daily for 20 days) showed a significant reduction or complete absence of cytoplasmic hepatitis B core antigen (HBeAg) in hepatocytes of both male and female mice, unlike 3TC treatment which did not show this effect. Nuclear HBeAg staining was not significantly affected by BAY 41-4109 treatment. [1] |
| Cell Assay |
The antiviral activity of BAY 41-4109 against HBV replication was assessed using HepG2.2.15 cells. Cells were plated in 96-well plates and incubated with serial dilutions of the compound at 37°C under 5% CO2. The culture medium was changed on day 4. After 8 days of exposure to the compounds, cell culture supernatants were collected, and cells were lysed. HBV-DNA present in the supernatants and/or lysates was quantified using dot-blot hybridization followed by chemiluminescent detection and analysis with an imaging system. The IC50 was calculated from this data. [1]
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| Animal Protocol |
Rodents: HBV-transgenic mice are used in this study. For a duration of 28 days, mice are administered the compounds (BAY 41-4109) twice daily in a suspension solution containing 0.5% tylose. 0.5% tylose serves as the placebo. After the animals are killed six hours after the last treatment, the livers are immediately removed and frozen for additional analysis. To get blood, punctures are made in the hearts of the unconscious animals[1].
HBV-transgenic mice (Tg [HBV1.3 fsX−3′5′]), approximately 10 weeks old, producing high levels of serum HBV-DNA, were used. Animals were pre-selected based on serum HBV-DNA levels. Compounds were formulated as a suspension in 0.5% Tylose (serving as a placebo/vehicle control). For the main efficacy study, groups of mice (5 males and 5 females per group) were treated orally (per os) with BAY 41-4109 or 3TC at doses of 7.5, 15, or 30 mg/kg, administered twice daily (b.i.d.) for 28 consecutive days. Animals were sacrificed 6 hours after the last dose. Livers were removed, frozen, and subsequently analyzed for HBV-DNA by dot-blot hybridization. Blood was collected via cardiac puncture, and plasma was analyzed for HBV-DNA by quantitative real-time PCR. [1] For immunohistochemical analysis of HBeAg, a separate experiment was conducted where mice were treated with 30 mg/kg of BAY 41-4109 or 3TC three times daily (t.i.d.) for 20 consecutive days. Livers were then fixed, paraffin-embedded, sectioned, and stained using an immunohistochemistry protocol involving a polyclonal rabbit antibody against HBeAg, followed by detection using an avidin-biotin-peroxidase system and 3,3'-diaminobenzidine as the chromogen. [1] |
| ADME/Pharmacokinetics |
In mice, BAY 41-4109 was rapidly absorbed after oral administration, with a time to peak concentration (tmax) of 0.17 hours. The oral bioavailability of BAY 41-4109 in mice was approximately 30%, while that in rats and dogs was approximately 60%. The clearance of this compound in mice was high and decreased with increasing animal size. The half-life in mice was approximately 2 hours. Based on the allometric growth ratios of animal data (mice, rats, and dogs), the predicted steady-state volume of distribution (Vss) in humans was 2.9 L/kg. Assuming complete absorption, the clearance and bioavailability in humans were also predicted using a scaling method. [1]
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| References |
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| Additional Infomation |
BAY 41-4109 ((R)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid methyl ester) is a novel non-nucleoside compound belonging to the heteroarylpyrimidine class. [1] Unlike the nucleoside analog 3TC, BAY 41-4109 can reduce cytoplasmic HBeAg levels, suggesting a unique antiviral mechanism that may involve direct inhibition of viral replication and/or inhibition of viral assembly. [1] This study concludes that, based on its potent antiviral activity in transgenic mouse models, favorable animal pharmacokinetic characteristics, and the lack of toxicity observed in the experiments conducted, BAY 41-4109 is a promising candidate drug for anti-HBV treatment. [1]
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| Molecular Formula |
C18H13CLF3N3O2
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|---|---|
| Molecular Weight |
395.7629
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| Exact Mass |
395.064
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| CAS # |
476617-51-3
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| Related CAS # |
Bay 41-4109;298708-81-3;Bay 41-4109 racemate;298708-79-9
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| PubChem CID |
10188768
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
645
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C([H])=C(C([H])=C([H])C=1[C@]1([H])C(C(=O)OC([H])([H])[H])=C(C([H])([H])[H])N([H])C(C2=C(C([H])=C(C([H])=N2)F)F)=N1)F
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| InChi Key |
FVNJBPMQWSIGJK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H13ClF3N3O2/c1-8-14(18(26)27-2)15(11-4-3-9(20)5-12(11)19)25-17(24-8)16-13(22)6-10(21)7-23-16/h3-7,15H,1-2H3,(H,24,25)
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| Chemical Name |
(S)-Methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
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| Synonyms |
BAY-414109 S-isomer; BAY414109 S-isomer; BAY 414109; BAY-41-4109; BAY41-4109; BAY 41-4109
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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 : ≥ 37 mg/mL (~93.49 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5268 mL | 12.6339 mL | 25.2678 mL | |
| 5 mM | 0.5054 mL | 2.5268 mL | 5.0536 mL | |
| 10 mM | 0.2527 mL | 1.2634 mL | 2.5268 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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