Description
Zileuton, a benzothiophene N-hydroxyurea, is the only approved inhibitor of 5-lipoxygenase. It is believed to intervene with allergic and inflammatory diseases by suppression of leukotriene (LT) biosynthesis. The compound belongs to the class of iron ligand-type inhibitors of 5-lipoxygenase that not only chelates the active site iron of the enzyme but also possesses weak-reducing properties.
Zileuton is used as a type of drug for the prophylaxis and chronic treatment of asthma.
References
[1] A Rossi, C Pergola, A Koeberle, M Hoffmann, F Dehm, P Bramanti, S Cuzzocrea, O Werz and L Sautebin, The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages, British Journal of Pharmacology, 2010, col. 161, 555-570
[2] SE Wenzel and AK Kamada, Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma, Ann Pharmacother., 1996, vol. 30, 858-864
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 IC
50 value of 0.5 μM. Zileuton inhibits leukotriene B
4 (LTB
4; ) production induced by the calcium ionophore A23187 in purified human peripheral blood polymorphonuclear leukocytes (PMNLs; IC
50 = 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 LTB
4,
LTE
4, LTD
4 and LTC
4. Zyflo has no effect on myeloperoxidase activity, neutrophil
degranulation, mast cell histamine release or phospholipase A
2 activities. It did not
inhibit cyclooxygenase as witnessed by the formation of TXB
2. 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
Uses
An inhibitor of 5-lipoxygenase, the initial enzyme in the biosynthesis of leukotrienes from Arachidonic Acid. Used as an antiasthmatic.
Uses
gastric acid secretion 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.
References
[1] G W CARTER. 5-lipoxygenase inhibitory activity of zileuton.[J]. Journal of Pharmacology and Experimental Therapeutics, 1991, 256 3: 929-937.
[2] A ROSSI. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages[J]. British Journal of Pharmacology, 2010, 161 3: 555-570. DOI:
10.1111/j.1476-5381.2010.00930.x
