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| Targets |
AVG-233 targets the RNA-dependent RNA polymerase (RdRp) of respiratory syncytial virus (RSV). By binding to the L1-1749 fragment of the polymerase, it prevents the initiation of the viral polymerase complex at the promoter. This inhibition blocks viral RNA synthesis and replication, making it a promising antiviral agent for RSV infections.
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| ln Vitro |
AVG-233 (1-100 μM) prevents 3'RNA elongation but does not obstruct up to three markers' 3'RNA elongation following reinitiation from the promoter or reverse initiation [1]. RSV A2-L19F (EC50=0.31 μM), RSV strain 2-20 (EC50=0.14 μM), and RSV clinical isolate 718 (EC50=0.2 μM) have lower viral yields when treated with AVG-233 (1.25–μM) [1]. 40 μM; 0-300 s) has an IC50 value of 13.7 μM and suppresses L1-1749 fragment RNA synthesis in a simulated coupling way. The L and L1-1749 segments have affinities similar to AVG-233 (dissociation distribution (KD) of 38.3 μM and 53.1 μM, respectively) [2].
In vitro, AVG-233 acts as a potent inhibitor of RNA-dependent RNA polymerase (RdRp). It prevents initiation of the viral polymerase complex at the promoter, blocking viral RNA synthesis. Its in vitro activity is assessed using biochemical assays that measure RdRp activity in the presence of the compound, as well as cell-based assays that measure viral replication in RSV-infected cells. |
| ln Vivo |
In an RSV model, AVG-233 (50–100 mg/kg; ig; once) lowers lung viral load [2]. With a maximal plasma concentration of roughly 2 μM, AVG-233 (2 – 20 mg/kg; intravenous and oral; single dose; model CD-1 mice) exhibits good oral bioavailability [1].
In vivo activity of AVG-233 has been demonstrated in animal models of RSV infection. As an orally active compound, it is administered orally and has shown efficacy in reducing viral replication and disease symptoms. Its in vivo activity is assessed by measuring reductions in viral titers, improvements in lung pathology, and survival in infected animals. |
| Enzyme Assay |
The in vitro enzyme assay for AVG-233 involves measuring its inhibitory activity against RNA-dependent RNA polymerase (RdRp) in cell-free systems. These assays use purified RdRp enzyme and measure the incorporation of nucleotides into RNA in the presence of the compound. The compound prevents initiation of the viral polymerase complex at the promoter, and its binding site is present in the L1-1749 fragment. Inhibitory potency (IC50) is determined by assessing the reduction in polymerase activity.
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| Cell Assay |
In vitro cellular assays for AVG-233 are performed using RSV-infected cell lines. These assays measure the compound's ability to inhibit viral replication by assessing viral RNA synthesis, plaque formation, or viral protein expression. The compound's potent antiviral activity is demonstrated by its ability to reduce viral titers in infected cells. These assays confirm its mechanism of action as an RdRp inhibitor.
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| Animal Protocol |
Animal/Disease Models: Female Balb/cJ mice with recRSV-mKate xenografts [2]
Doses: 50 and 100 mg/kg Route of Administration: po (oral gavage); Experimental Results: 0.89 log10 TCID50 reduction in lung viral load (median tissue culture infectious dose)/mL. Animal/Disease Models: Male CD-1 mice (27-29 g) [1] Doses: 2 mg/kg (iv) and 20 mg/kg (po) Route of Administration: intravenously (iv) (iv)(iv) and po (po (oral gavage)) once, before dosing and blood samples collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hrs (hrs (hours)) after administration. Experimental Results: 1.19 Route dose Tmax Cmax AUC0-∞ CL/F T1/2 Bioavailability mg/kg h nmol/ml h× nmol/ml liter/h/kg h % Oral 20 1 2.17 5.95 6.98 5.28 33.8 In vivo animal studies for AVG-233 are conducted in rodent models of RSV infection. These studies typically involve oral administration of the compound, followed by assessment of viral replication, lung pathology, and survival. The compound's oral bioavailability and efficacy are evaluated in these models, supporting its development as an antiviral agent for RSV. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of AVG-233 are characterized by oral activity and bioavailability. As an orally active compound, it is designed for systemic administration and has favorable ADME properties. Its pharmacokinetic profile supports once- or twice-daily dosing for the treatment of RSV infections. Detailed PK parameters such as half-life, Cmax, and AUC are determined in preclinical species.
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| Toxicity/Toxicokinetics |
Toxicology studies of AVG-233 have been conducted to evaluate its safety profile as an antiviral agent. These studies include acute and repeat-dose toxicity assessments in preclinical species, as well as genotoxicity and safety pharmacology evaluations. As an RdRp inhibitor targeting viral polymerase, it is expected to have a favorable safety profile with selectivity for viral over host enzymes.
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| References |
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| Additional Infomation |
AVG-233 is a potent, orally active RNA-dependent RNA polymerase (RdRp) inhibitor being studied for the treatment of respiratory syncytial virus (RSV) infections. It prevents initiation of the viral polymerase complex at the promoter, and its binding site is present in the L1-1749 fragment of the polymerase. The compound represents a promising approach for the treatment of RSV, a common respiratory pathogen.
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| Molecular Formula |
C26H22CLN5O3
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| Molecular Weight |
487.937584400177
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| Exact Mass |
487.141
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| CAS # |
2151937-80-1
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| PubChem CID |
132136732
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| Appearance |
Solid powder
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| LogP |
3.5
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
884
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=CC(CN2C(C=C3C(C(N(C4C=CC=CN=4)N3CC3C=CC(=CC=3)OC)=O)=C2C)=O)=N1
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| InChi Key |
CXZZYJLIYWCICH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H22ClN5O3/c1-17-25-21(14-24(33)30(17)16-19-6-5-7-22(27)29-19)31(15-18-9-11-20(35-2)12-10-18)32(26(25)34)23-8-3-4-13-28-23/h3-14H,15-16H2,1-2H3
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| Chemical Name |
5-[(6-chloropyridin-2-yl)methyl]-1-[(4-methoxyphenyl)methyl]-4-methyl-2-pyridin-2-ylpyrazolo[4,3-c]pyridine-3,6-dione
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 mg/mL (~102.47 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 | 2.0494 mL | 10.2472 mL | 20.4943 mL | |
| 5 mM | 0.4099 mL | 2.0494 mL | 4.0989 mL | |
| 10 mM | 0.2049 mL | 1.0247 mL | 2.0494 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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