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Zileuton sodium (also known as A-64077 sodium; Abbott-64077; ZYFLO; ZYFLO CR) is a novel, potent and orally bioactive inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation, it was introduced in 1996 to decrease the symptoms of asthma. Zileuton suppresses PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. Zileuton significantly reduces PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. Zileuton inhibits PGE2 production in LPS-stimulated human whole blood and suppresses PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy.
| Targets |
5-lipoxygenase (5-LO)
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|---|---|
| ln Vitro |
When zileuton sodium (A 64077 sodium) was added to anti-CD3-treated cells, IL-2 levels in both treated and untreated cells declined with longer incubation times. By blocking 5-lipoxygenase, zileutonodium (sodium A 64077) may lower IL-2 levels by preventing the synthesis of leukotriene B4, which is an IL-2 inducer [2].
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| ln Vivo |
The effect of zileuton sodium (sodium A 64077) (5 mg/kg, p.o.) on lowering NF-κB expression was not significantly affected by COX inhibitors in rats with I/R. Additionally, this group's NF-κB staining levels were noticeably lower. The apoptotic index of I/R rats treated with zileuton (5 mg/kg, orally) can be dramatically decreased. Regarding the rise in serum TNF-α levels in the I/R group, zileuton showed no discernible impact [1]. In the colon and small intestine of APCΔ468, zileutonodium (A 64077 sodium) (1200 mg/kg) suppresses the formation of polyps. In rat polyps, zileuton therapy increases the rate of apoptosis and decreases the rate of proliferation of non-epithelial cells. The small intestine and colon treated with zileuton showed a considerable increase in the amount of apoptotic cells. In zileuton-fed APCΔ468 mice, a decreased proliferation rate may play a major role in the reduction of small intestine and colon polyposis [3].
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| Cell Assay |
Spleen cells obtained from 11 4-month-old C57BL/6 female mice were incubated without and with 10 μg/mL HU or zileuton, 2.5 μg/mL concanavalin A (ConA), 20 μg/mL phytohemagglutinin (PHA), and 50 ng/mL anti-CD3 antibody for 12-48 h. IL-2 was measured in the supernatant by enzyme-linked immunosorbent assay and cell proliferation by (3)H-thymidine uptake[2].
Results: While HU reduced lymphocyte proliferation in response to mitogens (P<0.05), zileuton did not. Baseline IL-2 concentration and PHA-induced IL-2 were not significantly affected by either drug. Contrary to what we expected, while HU increased IL-2 supernatant levels 1.17-fold to 6.5-fold in anti-CD3 antibody-treated cells (P<0.05), zileuton decreased them 35%-65% (P<0.05). Zileuton likely reduced IL-2 levels by inhibiting 5-lipoxygenase, hence leukotriene B4 production, an IL-2 inducer. HU did not decrease IL-2 secretion likely because of its lack of effect on mRNA and protein synthesis[2].
Conclusion: Modulation of IL-2 secretion by zileuton and/or reduced lymphocyte proliferation by HU may impair the immune response of patients with sickle cell disease but may also be beneficial by attenuating inflammation independently of fetal hemoglobin induction[2].
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| Animal Protocol |
Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.[1]
In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.[3] |
| References |
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| Additional Infomation |
Zileuton is a member of the class of 1-benzothiophenes that is 1-benzothiophene in which the hydrogen at position 2 is replaced by a 1-[carbamoyl(hydroxy)amino]ethyl group. A selective 5-lipoxygenase inhibitor, it inhibits the formation of leukotrienes LTB4, LTC4, LDT4, and LTE4. It is used for the management of chronic asthma. It has a role as an EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor, a non-steroidal anti-inflammatory drug, an anti-asthmatic drug, a leukotriene antagonist and a ferroptosis inhibitor. It is a member of ureas and a member of 1-benzothiophenes. It derives from a hydride of a 1-benzothiophene.
Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. The immediate release tablet of Zileuton has been withdrawn from the US market. Zileuton is a 5-Lipoxygenase Inhibitor. The mechanism of action of zileuton is as a 5-Lipoxygenase Inhibitor. The physiologic effect of zileuton is by means of Decreased Leukotriene Production. Zileuton is an antiinflammatory leukotriene pathway inhibitor classified as an inhibitor of the enzyme 5-lipoxygenase that is used in the treatment of asthma and allergic rhinitis. Zileuton has been linked to rare cases of drug induced liver disease and is considered to be contraindicated in patients with active liver disease. View More
Zileuton is a synthetic derivative of hydroxyurea with antiasthmatic properties. The leukotriene inhibitor zileuton blocks 5-lipoxygenase, which catalyzes the formation of leukotrienes from arachidonic acid; causes bronchodilation; decreases bronchial mucous secretion and edema; and may prevent or decrease the symptoms of asthma. (NCI04)
Drug Indication For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Pharmacodynamics Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma. Absorption Rapidly and almost completely absorbed. The absolute bioavailability is unknown. Route of Elimination Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose. Volume of Distribution 1.2 L/kg Clearance Apparent oral cl=7 mL/min/kg Metabolism / Metabolites Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4. Zileuton has known human metabolites that include Zileuton O-glucuronide. S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560 Biological Half-Life 2.5 hours Mechanism of Action Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5-lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control. |
| Molecular Formula |
C11H11N2O2S-.NA+
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|---|---|
| Molecular Weight |
258.272
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| Exact Mass |
258.044
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| CAS # |
118569-21-4
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| Related CAS # |
Zileuton;111406-87-2;Zileuton-d4;1189878-76-9
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| PubChem CID |
78357785
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| Appearance |
White to off-white solid powder
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| LogP |
3.541
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
17
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| Complexity |
280
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
USURPRPAYRQEOV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H11N2O2S.Na/c1-7(13(15)11(12)14)10-6-8-4-2-3-5-9(8)16-10;/h2-7H,1H3,(H2,12,14);/q-1;+1
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| Chemical Name |
sodium;1-[1-(1-benzothiophen-2-yl)ethyl]-1-oxidourea
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| Synonyms |
Zileuton (sodium); 118569-21-4; sodium;1-[1-(1-benzothiophen-2-yl)ethyl]-1-oxidourea; Zileutonsodium; A 64077 (sodium);
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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, avoid exposure to moisture. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 3.8719 mL | 19.3596 mL | 38.7192 mL | |
| 5 mM | 0.7744 mL | 3.8719 mL | 7.7438 mL | |
| 10 mM | 0.3872 mL | 1.9360 mL | 3.8719 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01130688 | TERMINATED | Drug: Zileuton | Chronic Myelogenous Leukemia | University of Massachusetts,Worcester | 2010-01 | Phase 1 |
| NCT01136941 | COMPLETED | Drug: Zileuton | Sickle Cell Disease | Children's Hospital Medical Center, Cincinnati |
2010-09 | Phase 1 |
| NCT00534625 | COMPLETED | Drug:zileuton Drug:placebo |
Asthma | Critical Therapeutics | 2007-09 | Phase 2 |
| NCT04996199 | UNKNOWN STATUS | Drug:Oxcarbazepine Drug:Carbamazepine |
Trigeminal Neuralgia | Postgraduate Institute of Dental Sciences Rohtak |
2021-09-18 | Phase 4 |
| NCT00595114 | COMPLETED | Asthma Pulmonary Disease,Chronic Obstructive |
Brigham and Women's Hospital | 2007-12 |
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