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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)
Zileuton sodium selectively and reversibly inhibits 5-lipoxygenase (5-LOX). 5-LOX is a key enzyme in the arachidonic acid cascade that catalyzes the conversion of arachidonic acid to leukotriene A4 (LTA4), the precursor for all leukotrienes. By inhibiting 5-LOX, zileuton blocks the production of pro-inflammatory leukotrienes including LTB4 (a potent chemoattractant for neutrophils) and the cysteinyl leukotrienes LTC4, LTD4, and LTE4 (which cause bronchoconstriction, mucus secretion, and vascular permeability). The compound exhibits a high degree of selectivity for 5-LOX over other lipoxygenase isoforms and cyclooxygenases. |
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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].
Zileuton sodium inhibits 5-lipoxygenase with an IC₅0 value of 0.5 microM. In cellular assays, the compound effectively suppresses leukotriene B4 (LTB4) synthesis in stimulated human neutrophils and other leukocyte populations. The inhibition is reversible and competitive with the substrate arachidonic acid. Zileuton demonstrates concentration-dependent inhibition of 5-LOX activity in various cell types including polymorphonuclear leukocytes, macrophages, and mast cells. The compound shows no significant inhibitory activity against 12-lipoxygenase, 15-lipoxygenase, or cyclooxygenase-1 and -2 at concentrations up to 100 microM, confirming its selectivity for 5-LOX. |
| 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].
In vivo, Zileuton sodium significantly reduces arachidonic acid-induced ear edema in mice with an ED₅0 of 31 mg/kg. The compound prevents polyp formation efficiently by reducing tumor-associated and systemic inflammation in in vivo models. In animal models of asthma, zileuton attenuates antigen-induced bronchoconstriction, reduces airway hyperresponsiveness, and decreases leukotriene levels in bronchoalveolar lavage fluid. In models of inflammatory bowel disease, the compound reduces colonic inflammation and tissue damage. Zileuton also demonstrates efficacy in models of rheumatoid arthritis, psoriasis, and other inflammatory conditions. Clinical studies have confirmed its efficacy in reducing asthma symptoms and improving lung function. |
| Enzyme Assay |
In vitro enzyme assays for zileuton involve measuring 5-lipoxygenase activity using isolated enzyme preparations or cell lysates. The enzyme is typically incubated with arachidonic acid substrate and the test compound in assay buffer containing calcium, ATP, and glutathione. After incubation at 37degC for 10-30 minutes, the reaction is stopped by acidification. The products (5-HETE and leukotrienes) are extracted and quantified by HPLC with UV detection or by radioimmunoassay. Alternatively, a spectrophotometric assay monitoring the formation of conjugated dienes at 234 nm can be used for kinetic studies. IC₅0 values are determined from dose-response curves using nonlinear regression. The sodium salt form dissolves readily in aqueous buffers.
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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].
Cellular assays for zileuton sodium are performed using human polymorphonuclear leukocytes (PMNs), monocytes, or mast cells stimulated with calcium ionophore A23187 or opsonized zymosan. Cells are isolated from whole blood by density gradient centrifugation and resuspended in HBSS buffer. Following pre-incubation with serial dilutions of zileuton (0.01-100 microM) for 10-15 minutes, cells are stimulated with 5-10 microM calcium ionophore A23187 at 37degC for 10-30 minutes. The reaction is terminated by centrifugation and the supernatant is collected. LTB4 and other leukotrienes are quantified by ELISA or LC-MS/MS. IC₅0 values for inhibition of leukotriene production are calculated from dose-response curves. |
| 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] In vivo efficacy studies for zileuton are conducted in rodent models of inflammation. For the arachidonic acid-induced ear edema model, mice are treated orally with zileuton (10-100 mg/kg) or vehicle 30-60 minutes prior to topical application of arachidonic acid (2 mg/ear) to the right ear. Left ear receives vehicle as control. After 1 hour, ear punch biopsies are taken and edema is measured by ear weight or thickness difference. ED₅0 values are calculated from dose-response curves. In asthma models, sensitized guinea pigs or mice are challenged with aerosolized antigen, and bronchoconstriction or airway hyperresponsiveness is measured using plethysmography. Leukotriene levels in BAL fluid are quantified by ELISA. |
| ADME/Pharmacokinetics |
Zileuton sodium (CAS#: 118569-21-4) has molecular formula C11H11N2NaO2S and molecular weight 258.27. The compound is soluble in DMSO at ≥16.67 mg/mL and in ethanol at ≥16.43 mg/mL, but is insoluble in water. Zileuton is orally bioavailable with peak plasma concentrations reached 1-3 hours post-administration. It undergoes extensive hepatic metabolism, primarily via CYP1A2 and CYP2C9, with an elimination half-life of approximately 2-5 hours. The compound is excreted in urine and feces as metabolites. In clinical use, zileuton is administered as 600 mg tablets four times daily.
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| Toxicity/Toxicokinetics |
Toxicological information for zileuton sodium: The compound is generally well-tolerated in preclinical and clinical studies. Common adverse effects include headache, nausea, and gastrointestinal disturbances. Elevations in liver enzymes (ALT, AST) have been observed in some patients, requiring periodic liver function monitoring. In animal studies, zileuton shows low acute toxicity with oral LD₅0 > 2000 mg/kg in rodents. No significant mutagenic or carcinogenic effects have been reported. The compound should be handled with standard laboratory precautions including the use of personal protective equipment. For research use, zileuton sodium is supplied as a high-purity compound and should be stored desiccated at -20degC, protected from light.
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| References |
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| Additional Infomation |
Zileuton belongs to the 1-benzothiophene class of compounds, with its structure consisting of a hydrogen atom at the 2-position of the 1-benzothiophene molecule replaced by a 1-[carbamoyl(hydroxy)amino]ethyl group. It is a selective 5-lipoxygenase inhibitor that inhibits the production of leukotrienes LTB4, LTC4, LDT4, and LTE4. Zileuton is used to treat chronic asthma. It possesses various pharmacological activities, including as an EC 1.13.11.34 (arachidonic acid 5-lipoxygenase) inhibitor, a nonsteroidal anti-inflammatory drug, an anti-asthmatic drug, a leukotriene antagonist, and a ferroptosis inhibitor. It belongs to the urea and 1-benzothiophene classes of compounds. It is derived from the hydride of 1-benzothiophene. Leukotrienes are a class of substances that can induce a variety of biological effects, including enhancing the migration of neutrophils and eosinophils, promoting the aggregation of neutrophils and monocytes, enhancing leukocyte adhesion, increasing capillary permeability, and inducing smooth muscle contraction. These effects lead to airway inflammation, edema, mucus secretion, and bronchoconstriction in asthma patients. Zileuton alleviates these symptoms by selectively inhibiting 5-lipoxygenase (an enzyme that catalyzes the conversion of arachidonic acid into leukotrienes). Specifically, it inhibits the production of leukotrienes LTB4, LTC4, LTD4, and LTE4. Both R(+) and S(-) enantiomers exhibit pharmacological activity as 5-lipoxygenase inhibitors in in vitro systems. Zileuton immediate-release tablets have been withdrawn from the US market. Zileuton is a 5-lipoxygenase inhibitor. Its mechanism of action is the inhibition of 5-lipoxygenase. Its physiological effect is through reducing leukotriene production. Zileuton is an anti-inflammatory leukotriene pathway inhibitor, belonging to the 5-lipoxygenase inhibitor class, used to treat asthma and allergic rhinitis. Zileuton has been associated with rare cases of drug-induced liver disease and is therefore considered contraindicated in patients with active liver disease.
View MoreZiliutone is a synthetic derivative of hydroxyurea with anti-asthmatic properties. As a leukotriene inhibitor, ziliutone blocks 5-lipoxygenase (which catalyzes the formation of leukotrienes from arachidonic acid), thereby causing bronchodilation, reducing bronchial mucus secretion and edema, and may prevent or alleviate asthma symptoms. (NCI04) Drug Indications For the prevention and chronic treatment of asthma in adults and children aged 12 years and older. Pharmacodynamics Ziliutone is an asthma medication with chemical and pharmacological properties that differ from other anti-asthma medications. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase (an enzyme in the eicosate synthesis pathway). Current data indicate that asthma is a chronic inflammatory airway disease involving the production and activity of various endogenous inflammatory mediators, including leukotrienes. Thiopeptide leukotrienes (LTC4, LTD4, LTE4, also known as sustained-release substances of anaphylactic reactions) and LTB4 (a chemokine for neutrophils and eosinophils) are both derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be detected in various biological fluids, including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileutone reduces bronchoconstriction induced by cold air provocation in asthmatic patients. Absorption Absorption is rapid and almost complete. Absolute bioavailability is unknown. Elimination pathway Zileutone is primarily eliminated through metabolism, with a mean terminal half-life of 2.5 hours. The urinary excretion of both the inactive N-dehydroxylated metabolite and the unchanged zileuton is less than 0.5% of the administered dose. Volume of distribution 1.2 L/kg Clearance Apparent oral clearance = 7 mL/min/kg Metabolites/Metabolites Hepatic metabolism. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by cytochrome P450 isoenzymes 1A2, 2C9, and 3A4. Known human metabolites of zileuton include zileuton O-glucuronide. S73 | METXBIODB | Metabolite Response Database from BioTransformer | DOI:10.5281/zenodo.4056560 Biological Half-Life 2.5 hours Mechanism of Action Leukotrienes are a class of substances that can induce a variety of biological effects, including enhancing neutrophil and eosinophil migration, promoting neutrophil and monocyte aggregation, enhancing leukocyte adhesion, increasing capillary permeability, and causing smooth muscle contraction. These effects lead to airway inflammation, edema, mucus secretion, and bronchoconstriction in asthmatic patients. Ziliutone alleviates these symptoms by selectively inhibiting 5-lipoxygenase (an enzyme that catalyzes the conversion of arachidonic acid into leukotrienes). Specifically, it inhibits the production of leukotrienes LTB4, LTC4, LTD4, and LTE4. Both R(+) and S(-) enantiomers exhibit pharmacological activity as 5-lipoxygenase inhibitors in in vitro systems. Since leukotrienes play a role in the pathogenesis of asthma, regulating leukotriene production by blocking 5-lipoxygenase activity may alleviate airway symptoms, reduce bronchial smooth muscle tone, and improve asthma control. Zileuton sodium (CAS#: 118569-21-4) is a clinically approved antiasthmatic agent marketed under the brand name Zyflo for the prophylaxis and chronic treatment of asthma. It was the first 5-lipoxygenase inhibitor approved by the FDA. The mechanism of action involves selective inhibition of 5-LOX, reducing leukotriene production and thereby decreasing bronchoconstriction, mucus secretion, and airway inflammation. Zileuton is used as a monotherapy or in combination with other antiasthmatic medications. The sodium salt formulation is used primarily in research settings. The compound is also investigated for potential applications in other inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, and psoriasis. For research use only, not for human therapeutic applications without appropriate authorization. |
| 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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| SMILES |
CC(C1=CC2=CC=CC=C2S1)N(C(=O)N)[O-].[Na+]
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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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