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| Targets |
Zardaverine targets phosphodiesterase type 3 (PDE3) and type 4 (PDE4). PDE3 and PDE4 are key enzymes responsible for the hydrolysis of cyclic nucleotides cAMP and cGMP. By inhibiting these enzymes, Zardaverine increases intracellular cAMP levels, leading to smooth muscle relaxation (bronchodilation) and anti-inflammatory effects. The dual inhibition of PDE3 and PDE4 provides synergistic bronchodilator and anti-inflammatory activities, making it effective in asthma. Interestingly, Zardaverine also shows selective antitumor activity against HCC cells that is independent of PDE3/4 inhibition, suggesting additional mechanisms of action.
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| ln Vitro |
Human HCC cell proliferation is specifically inhibited in vitro by zardaverine (0-30 µM; 72 hours) [1]. While not connected to PDE3/4 inhibition, zardaverine exhibits specific anti-tumor activity that is intimately linked to the control of cell cycle-related proteins [1]. In HCC cells, zardaverine (0.1 µM; 24 hours) specifically induces G0/G1 phase arrest and dysregulates proteins linked to the cell cycle [1]. In Bel-7402 and SMMC-7721 cells, zardaverine (0.01, 0.03, 0.1, 0.3 1 µM/48h; 0.3 1 µM/24, 36, 48, 60, 72 h) causes apoptosis in a time- and concentration-dependent manner [1].
In vitro, Zardaverine (0-30 µM; 72 h) selectively inhibits the growth of human hepatocellular carcinoma (HCC) cells. It shows selective antitumor activity that is closely related to the regulation of cell cycle-associated proteins but is independent of PDE3/4 inhibition. Zardaverine (0.1 µM; 24 h) selectively causes G0/G1-phase arrest and dysregulates cell cycle-associated proteins in HCC cells. It induces apoptosis in a time- and concentration-dependent manner in Bel-7402 and SMMC-7721 cells. The compound inhibits the growth of various HCC cell lines with IC50s of 36.6 µM (SMMC-7721), 51.0 µM (QGY-7701), 137.7 µM (Bel-7402), and 288.0 µM (Bel-7404). |
| ln Vivo |
Mice bearing human Bel-7402 xenografts are unable to grow without the oral drug zardaverine (60, 200 mg/kg; once daily for 14 days) [1]. A rat model of airway inflammation and hyperresponsiveness shows 100% blocking of LPS-induced increases in responsiveness when treated with zardaverine (8046.6 µg/kg; i.p.; single dosage) [2].
In vivo, Zardaverine has bronchodilator activity and is effective in bronchial relaxation and reduction of inflammation in asthma. The compound is orally active and has good antitumor potential. Detailed in vivo efficacy data from animal models are not extensively reported in the available literature, but its bronchodilator effects have been demonstrated in preclinical models of asthma. Its antitumor potential has also been evaluated in vivo. |
| Enzyme Assay |
Non-cell-based enzyme assays for Zardaverine use purified PDE3 and PDE4 enzymes. The compound is incubated with the enzyme, a cyclic nucleotide substrate (e.g., cAMP or cGMP), and cofactors at varying concentrations. PDE activity is measured by quantifying the hydrolysis of the cyclic nucleotide to its corresponding monophosphate using radiometric, fluorescence-based, or HPLC methods. IC50 values for enzyme inhibition are determined from dose-response curves. Selectivity for PDE3 and PDE4 over other PDE isoforms is also assessed.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Bel-7402, Bel-7404, QGY-7701 and SMMC-7721 Tested Concentrations: 0-30 µM Incubation Duration: 72 hrs (hours) Experimental Results: Selective inhibition of SMMC-7721, QGY-7701, Bel- For the growth of 7402 and Bel-7404, the IC50 were 36.6, 51.0, 137.7 and 288.0 respectively. Cell cycle analysis[1] Cell Types: Bel-7402, Bel-7404, QGY-7701 and SMMC-7721 Tested Concentrations: 0.1 µM Incubation Duration: 24 hrs (hours) Experimental Results: Induction of Bel-7402, Bel-7404, QGY-7701 and SMMC- Accumulation of 7721 SMMC-7721 cells are in G0/G1 phase. Western Blot Analysis[1] Cell Types: Bel-7402, SMMC-7721 Tested Concentrations: 0.01, 0.03, 0.1, 0.3 1 µM; 0.3 1 µM Incubation Duration: 48 hrs (hours); 24, 36, 48, 60, 72 hrs (hours) Experimental Results: Induction Concentration- and time-dependent increase in cleavage of PARP and caspase-3, -8, and -9 (apoptotic markers). Cellular assays for Zardaverine utilize HCC cell lines such as Bel-7402, Bel-7404, QGY-7701, and SMMC-7721. Cells are treated with the compound at various concentrations (0-30 µM) for specified durations (e.g., 24-72 hours). Cell proliferation is assessed using standard viability assays (e.g., MTT, CCK-8) to determine IC50 values. Cell cycle analysis is performed by flow cytometry after propidium iodide staining to confirm G0/G1 arrest. Apoptosis is evaluated using Annexin V/PI staining or caspase activity assays. Protein expression changes (cell cycle-associated proteins) are analyzed by Western blotting. |
| Animal Protocol |
Animal/Disease Models: Female Balb/cA nude mice (5 to 6 weeks old; human Bel-7402 xenograft model) [1].
Doses: 60, 200 mg/kg Route of Administration: Oral; one time/day for 14 days Experimental Results: The 60 mg/kg dose inhibited the growth of Bel-7402 xenografts for 14 days, and the 200 mg/kg dose caused tumor regression. Animal/Disease Models: Inbred male Fisher 344 (F344) rat (250-350 g; 3 to 4 months old; airway inflammation and hyperresponsiveness model) [2]. Doses: 8046.6 µg/kg (30 µmol/Kg) Route of Administration: intraperitoneal (ip) injection; single Experimental Results:complete blocking of LPS-induced hyperresponsiveness and airway inflammation. In vivo animal models for Zardaverine include models of asthma and HCC xenografts. For asthma, standard models such as ovalbumin-induced airway hyperresponsiveness in guinea pigs or mice are used. The compound is administered orally, and bronchodilation is assessed by measuring airway resistance or other respiratory parameters. For antitumor studies, xenograft models in immunodeficient mice bearing human HCC cell lines are used. Tumor growth inhibition is monitored over time. Detailed protocols are not extensively reported in the available literature. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Zardaverine include a molecular weight of 268.22 g/mol and molecular formula C12H10F2N2O3. CAS number is 101975-10-4. The compound is orally active. Purity is ≥98%. Storage conditions: powder at -20°C for 3 years; in solvent at -80°C for 2 years. Detailed PK parameters such as half-life, bioavailability, and volume of distribution are not extensively reported in the available literature.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for Zardaverine are not extensively reported in the available literature. As a research compound, its safety profile would need to be established through standard preclinical toxicity assessments. The compound is supplied for research use only and not for human consumption. Given its PDE3/4 inhibition mechanism, potential cardiovascular effects (related to PDE3 inhibition) would be a key safety consideration. Standard toxicity assessments would include evaluation of cardiovascular function, as well as hematological, hepatic, and renal parameters.
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| References | |
| Additional Infomation |
Zadavirin is a pyridazinone derivative in which the C-6 position of pyridazin-3(2H)-one is substituted with 4-(difluoromethoxy)-3-methoxyphenyl. It is a phosphodiesterase inhibitor, selective for both PDE3 and PDE4. It can be used as an EC 3.1.4. (phosphodiester hydrolase) inhibitor, a peripheral nervous system drug, an anti-asthmatic drug, and a bronchodilator. It is an organofluorine compound and also a pyridazinone compound.
Zardaverine is also known as a dual-selective PDE3/4 inhibitor and is cataloged under CAS number 101975-10-4. It is a pyridazinone derivative with potent bronchodilator activity. It has IC50 values of 0.58 µM for PDE3 and 0.17 µM for PDE4. Zardaverine possesses bronchodilatory activity and exhibits therapeutic effects against asthma. It also selectively inhibits the proliferation of HCC cells and induces apoptosis and cell cycle arrest, showing good antitumor potential. It is used for research purposes only. |
| Molecular Formula |
C12H10N2O3F2
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| Molecular Weight |
268.2162
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| Exact Mass |
268.065
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| CAS # |
101975-10-4
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| PubChem CID |
5723
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.555
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| LogP |
0.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
19
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| Complexity |
398
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HJMQDJPMQIHLPB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H10F2N2O3/c1-18-10-6-7(2-4-9(10)19-12(13)14)8-3-5-11(17)16-15-8/h2-6,12H,1H3,(H,16,17)
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| Chemical Name |
3-[4-(difluoromethoxy)-3-methoxyphenyl]-1H-pyridazin-6-one
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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 : ~25 mg/mL (~93.21 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.75 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 (7.75 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7283 mL | 18.6414 mL | 37.2828 mL | |
| 5 mM | 0.7457 mL | 3.7283 mL | 7.4566 mL | |
| 10 mM | 0.3728 mL | 1.8641 mL | 3.7283 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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