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Purity: ≥98%
BAY 41-4109 racemate is the racemic mixture of BAY 41-4109 which 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 |
HBV(IC50= 53 nM )
In vitro, BAY 41-4109 has the capacity to misdirect and speed up capsid assembly. BAY 41-4109 stabilizes formed capsids up to a ratio of one inhibitor molecule for every two dimers [2]. In HepG2.2.15 cells, BAY 41-4109 exhibits an equivalent level of efficacy in suppressing HBV DNA release and cytoplasmic HBcAg levels, with IC50 values of 32.6 and 132 nM, respectively. The dose-dependent inhibition of HBV DNA and HBcAg suggests that the anti-HBV mechanisms are linked to and reliant on the rate of HBcAg inhibition[3]. |
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| ln Vitro |
In vitro, BAY 41-4109 has the capacity to misdirect and speed up capsid assembly. BAY 41-4109 stabilizes formed capsids up to a ratio of one inhibitor molecule for every two dimers [2]. In HepG2.2.15 cells, BAY 41-4109 exhibits an equivalent level of efficacy in suppressing HBV DNA release and cytoplasmic HBcAg levels, with IC50 values of 32.6 and 132 nM, respectively. The dose-dependent inhibition of HBV DNA and HBcAg suggests that the anti-HBV mechanisms are linked to and reliant on the rate of HBcAg inhibition[3].
In experiments using 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 the HepG2.2.15 cells was 7 µM. [1] |
| ln Vivo |
With an efficacy similar to 3TC, BAY 41-4109 decreases viral DNA in the liver and plasma in a dose-dependent manner. Hepatitis B virus core antigen (HBcAg) in the livers of HBV-transgenic mice is decreased by BAY 41 -4109. Research on pharmacokinetics in mice has demonstrated quick absorption, a 30% bioavailability, and dose-proportional plasma concentrations in rats and dogs of roughly 60%[1]. By targeting the viral capsid, BAY41-4109 inhibits the production of viruses in vivo[2].
In HBV-transgenic mice (Tg [HBV1.3 fsX-3'5']), oral administration of BAY 41-4109 at 15 mg/kg and 30 mg/kg twice daily (b.i.d.) for 28 days significantly reduced HBV-specific DNA levels in the liver, as measured by dot-blot hybridization. The reduction was more pronounced at 30 mg/kg. [1] In the same model, BAY 41-4109 treatment at 15 mg/kg and 30 mg/kg b.i.d. for 28 days also significantly reduced HBV-DNA levels in the plasma, as quantified by real-time PCR. The antiviral effect in plasma was more pronounced than in the liver. [1] BAY 41-4109 (30 mg/kg, three times daily for 20 days) significantly reduced cytoplasmic hepatitis B virus core antigen (HBeAg) staining in the livers of both male and female transgenic mice, as assessed by immunohistochemistry. In contrast, treatment with the nucleoside analogue 3TC did not reduce cytoplasmic HBeAg. [1] The antiviral activity of BAY 41-4109 in reducing liver and plasma HBV-DNA was more effective than that of 3TC administered at 30 mg/kg b.i.d. in the transgenic mouse model. [1] |
| Cell Assay |
MTT colorimetry is used to measure cellular metabolism. In 96-well plates, HepG2.2.15 cells are plated at a density of 2 × 103 cells per well. 20 μL of MTT solution (5 g/L) is added to each well after 8 days of treatment with varying concentrations of each antiviral compound, and the wells are then incubated for 4 hours at 37°C. To dissolve the crystals, 150 μL of DMSO is then added and stirred for 10 minutes. An ELISA reader is used to record absorbance values at 490 nm. The curve regression equation is used to compute the MTT values[3].
The antiviral activity of compounds was assessed in a HepG2.2.15 cell-based assay. HepG2.2.15 cells were plated in 96-well plates and incubated with serial dilutions of the test compound. The medium was changed on day 4. On day 8, the cell culture supernatants were collected and the cells were lysed. The presence of HBV-DNA in the supernatants and cell lysates was detected and quantified using dot-blot hybridization followed by chemiluminescent detection and analysis with an imaging system. [1] |
| Animal Protocol |
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].
For efficacy studies, HBV-transgenic mice (Tg [HBV1.3 fsX-3'5']) were used. Mice were pre-selected for serum HBV-DNA levels. Groups consisted of 5 male and 5 female mice (~10 weeks old). [1] BAY 41-4109 was formulated as a suspension in 0.5% Tylose (a placebo control was 0.5% Tylose alone). [1] The compound suspension was administered orally (per os) to the mice. In the main efficacy study, it was given twice daily (b.i.d.) for 28 consecutive days at doses of 3, 7.5, 15, and 30 mg/kg. [1] In another experiment comparing effects on HBeAg, BAY 41-4109 was administered at 30 mg/kg three times daily (t.i.d.) for 20 consecutive days. [1] Mice were sacrificed 6 hours after the last treatment. Blood was collected via cardiac puncture, and livers were removed and immediately frozen for subsequent analysis of HBV-DNA and histology. [1] For pharmacokinetic studies, blood was collected from mice at various time points after intravenous and oral administration of BAY 41-4109 (three animals per time point). [1] |
| ADME/Pharmacokinetics |
In mice, BAY 41-4109 is a drug with high clearance. After oral administration, it is rapidly absorbed, with a time to peak concentration (tmax) of 0.17 hours. [1] The bioavailability of BAY 41-4109 in mice after oral administration is approximately 30%. [1] The half-life of BAY 41-4109 in mouse plasma is approximately 2 hours. [1] In rats and dogs, the oral bioavailability is approximately 60%, and absorption is also rapid (tmax = 0.17 hours in rats and 0.8 hours in dogs). [1] Using animal data, human pharmacokinetic parameters (clearance and volume of distribution) were predicted using allometric scaling. The predicted steady-state volume of distribution (Vss) was 2.9 L/kg. [1]
After precipitating the protein with acetonitrile, the concentration of BAY 41-4109 in plasma was determined by liquid chromatography-tandem mass spectrometry (LC/MSMS). [1] |
| 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) belongs to a class of novel heteroarylpyrimidine compounds and has been shown to be a potent inhibitor of hepatitis B virus (HBV) replication. [1]
Its mechanism of action appears to differ from that of nucleoside analogs (such as 3TC), as it can reduce the level of HBeAg in the cytoplasm of hepatocytes, an effect that 3TC does not possess. Its activity may stem from direct inhibition of viral replication mechanisms and/or inhibition of viral assembly processes. [1] This compound exhibits dose-dependent antiviral efficacy in transgenic mouse models of HBV replication, reducing viral DNA levels in the liver and plasma. [1] |
| Molecular Formula |
C18H13CLF3N3O2
|
|---|---|
| Molecular Weight |
395.76
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| Exact Mass |
395.06
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| Elemental Analysis |
C, 54.63; H, 3.31; Cl, 8.96; F, 14.40; N, 10.62; O, 8.09
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| CAS # |
298708-79-9
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| Related CAS # |
Bay 41-4109;298708-81-3;Bay 41-4109 (less active enantiomer);476617-51-3
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| PubChem CID |
9865484
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| Appearance |
Light yellow to yellow solid powder
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| Melting Point |
126 °C
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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 |
0
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| SMILES |
O=C(C1=C(C)N=C(C2=NC=C(F)C=C2F)NC1C3=CC=C(F)C=C3Cl)OC
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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 |
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; BAY414109; 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 : 50~79 mg/mL ( 126.34~199.61 mM )
Ethanol : ~11 mg/mL Water : ˂1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.32 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: 2.5 mg/mL (6.32 mM) (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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