Zileuton

Absorption

Rapidly and almost completely absorbed. The absolute bioavailability is unknown.

Toxicity

Minimum oral lethal dose of zileuton in various preparations was 500-4000 mg/kg in mice and 300-1000 mg/kg in rats (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively).

Description

Zileuton is a reversible 5-lipoxygenase (5-LO) inhibitor. It inhibits 5-LO activity in rat basophilic leukemia-1 (RBL-1) cell supernatant with an IC₅₀ value of 0.5 μM. Zileuton inhibits leukotriene B₄ (LTB₄; ) production induced by the calcium ionophore A23187 in purified human peripheral blood polymorphonuclear leukocytes (PMNLs; IC₅₀ = 0.6 μM). Zileuton (10 mg/kg, p.o.) prevents antigen challenge-induced increases in specific lung resistance in a sheep model of asthma at 4 to 8 hours post-challenge following administration 2 hours pre-challenge. Formulations containing zileuton have been used in the prophylaxis and chronic treatment of asthma.

Description

Zyflo was launched in the US for chronic asthma. It can be prepared in three steps from 2-acetylbenzo[b]thiophene. Zyflo is a reversible direct inhibitor of 5- lipoxgenase that is orally-active. It was able to effect a 70-100 YO reduction in LTB₄, LTE₄, LTD₄ and LTC₄. Zyflo has no effect on myeloperoxidase activity, neutrophil degranulation, mast cell histamine release or phospholipase A₂ activities. It did not inhibit cyclooxygenase as witnessed by the formation of TXB₂. It significantly attentuated asthmatic response to cold dry air, inhibited exercise-induce bronchoconstriction, and attenuated induced bronchospasms. Zyflo has antiinflammatory effects as witnessed by a decrease in edema, mucus production and cellular infiltration. It had a bronchodilatory effect within 2 h and increased spirometry results by 18%.

Chemical properties

Crystalline Solid

Originator

Abbott (US)

The Uses of Zileuton

An inhibitor of 5-lipoxygenase, the initial enzyme in the biosynthesis of leukotrienes from Arachidonic Acid. Used as an antiasthmatic

The Uses of Zileuton

gastric acid secretion inhibitor

The Uses of Zileuton

An inhibitor of 5-lipoxygenase, the initial enzyme in the biosynthesis of leukotrienes from Arachidonic Acid. Used as an antiasthmatic.

Background

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.

Indications

For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.

What are the applications of Application

Zileuton is a 5-LO (5-lipoxygenase) inhibitor

Definition

ChEBI: 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, LDT , and LTE4. It is used for the management of chronic asthma.

Manufacturing Process

N-Hydroxy-N-(1-benzo[b]thien-2-ylethyl) acetamide
1. 2-Acetyl benzo[b]thiophene.
Method a. Benzo[b]thiophene (10 g, 75 mmole) was dissolved in THF (50 ml) and cooled to -78°C. n-Butyl lithium (28 ml, 2.7 M in hexanes) was added. The mixture was stirred for 15 minutes and N,O-dimethyl acetohydroxamic acid was added. Following an additional 30 minutes of stirring, the reaction was quenched at -78°C with ethanol and 2 N HCl solution and extracted into ether. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with 20% ether in pentane to yield 6.9 g of the desired product as a white solid.
Method b. To a solution of benzo[b]thiophene (10.0 g, 75 mmole) in THF (50 ml) was added n-butyl lithium (33 ml, 2.5 M in hexanes) at -70°C under N 2 . The mixture, containing a white precipitate, was stirred at 70°C for 1 hour. Acetaldehyde (4.6 ml, 82 mmole) was added dropwise. After a few minutes the reaction was quenched with saturated NH 4 Cl solution. The layers were separated, the organic layer dried over MgSO4, filtered, and evaporated to give a white solid (10 g) which was used directly for the next step.
The alcohol prepared as described above (1.0 g) in acetone (50 ml) was cooled to 5°C and Jones Reagent was added dropwise until the orange yellow color persisted (1.4 ml). The reaction mixture was diluted with water and the desired product precipitated. It was collected by filtration to give 0.85 g.
2. 2-Acetyl benzo[b]thiophene oxime.
2-Acetyl benzo[b]thiophene (5 g, 28.4 mmole), prepared as described in step 1 above, and hydroxylamine hydrochloride (3.0 g, 42.6 mmole) were dissolved in a mixture of ethanol (50 ml) and pyridine (50 ml) and allowed to stir at room temperature for 2 hours. Most of the solvent was removed in vacuo and the residue dissolved in ether. After washing with 2 N HCl (100 ml), the solution was dried over MgSO 4 and evaporated. A white crystalline solid was obtained and was carried on without further purification. An alternative work-up may also be used. The reaction mixture was diluted with water (300 ml) and the product precipitated. It was filtered off and dried in vacuo.
3. 1-Benzo[b]thien-2-ylethyl hydroxylamine. The oxime prepared as in step 2 above (3.5 g, 18.5 mmole) was dissolved in ethanol (25 ml) and cooled to 0°C. Borane pyridine complex (3.7 ml, 37 mmole) was added via syringe under nitrogen followed 10 minutes later by 20% HCl in ethanol (30 ml). Within 30 minutes the reaction was complete and was brought to pH 9 with the addition of solid sodium carbonate or 2 N NaOH. The mixture was extracted into ether and dried over MgSO 4 . After evaporation a white solid (3.0 g) was obtained. This was carried on without further purification.
N-Hydroxy-N-(1-benzo[b]thien-2-ylethyl)urea
Method A. 1-Benzo[b]thien-2-yl ethyl hydroxyl amine prepared as described above, step 3 (2.0 g, 10 mmole), was refluxed for 30 minutes with trimethylsilyl isocyanate (1.65, 14.2 mmole) in dioxane (30 ml). The reaction mixture was then washed with saturated NH 4 Cl solution, dried with MgSO 4 , and evaporated.
Method B. 1-Benzo[b]thien-2-yl ethyl hydroxyl amine prepared as described in step 3, was dissolved in toluene (100 ml) and HCl gas was bubbled through the mixture at a moderate rate for about 4 minutes. The solution was then heated to reflux and phosgene was bubbled through for another 4 minutes. After an additional one hour reflux, the mixture was allowed to cool to room temperature and then added to excess cold ammonium hydroxide solution. The precipitate was collected and recrystallized. Melting point: 157°-158°C. NMR (300 MHz), and mass spectrum confirmed the structure of the prepared compound.

brand name

Zyflo (Sensus).

Therapeutic Function

Antiallergic, Antiinflammatory

Biological Activity

Orally active 5-lipoxygenase (5-LOX) inhibitor that inhibits LTB 4 synthesis (IC 50 values are 0.56, 2.3 and 2.6 μ M in dog, rat and human blood respectively). Inhibits antigen-induced contraction of tracheal strips in vitro (IC 50 = 6 μ M) and exhibits antiasthmatic activity in vivo . Also weakly inhibits CYP1A2 (K i = 66 - 98 μ M).

Biochem/physiol Actions

Zileuton is an anti-asthmatic, an inhibitor of 5-lipoxygenase; the initial enzyme in the biosynthesis of leukotrienes from arachidonic acid.

Pharmacokinetics

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.

Metabolism

Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4.

storage

Store at +4°C

References

1) Carter et al. (1991), 5-Lipoxygense inhibitory activity of zileuton; J. Pharmacol. Exp. Ther. 256 929 2) Rossi et al. (2010), The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages; Br. J. Pharmacol. 161 555