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Identification
NameZileuton
Accession NumberDB00744  (APRD00265)
TypeSmall Molecule
GroupsApproved, Investigational, Withdrawn
Description

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 The immediate release tablet of Zileuton has been withdrawn from the US market.

Structure
Thumb
Synonyms
(+-)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea
Leutrol
N-(1-Benzo(b)thien-2-ylethyl)-N-hydroxyurea
N-[1-(Benzo[b]thiophen-2-yl)ethyl]-N-hydroxyurea
Zileuton
Zileuton
Zileutonum
Zyflo
External Identifiers
  • A 64077
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zyflotablet600 mg/1oralChiesi USA, Inc.1996-12-06Not applicableUs
Zyflo CRtablet, multilayer, extended release600 mg/1oralChiesi USA, Inc.2007-05-30Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIV1L22WVE2S
CAS number111406-87-2
WeightAverage: 236.29
Monoisotopic: 236.061948328
Chemical FormulaC11H12N2O2S
InChI KeyInChIKey=MWLSOWXNZPKENC-UHFFFAOYSA-N
InChI
InChI=1S/C11H12N2O2S/c1-7(13(15)11(12)14)10-6-8-4-2-3-5-9(8)16-10/h2-7,15H,1H3,(H2,12,14)
IUPAC Name
1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea
SMILES
CC(N(O)C(N)=O)C1=CC2=CC=CC=C2S1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzothiophenes. These are organic compounds containing a benzene fused to a thiepine ring (a five-membered ring with six carbon atoms and one sulfur atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzothiophenes
Sub ClassNot Available
Direct ParentBenzothiophenes
Alternative Parents
Substituents
  • Benzothiophene
  • 2,3,5-trisubstituted thiophene
  • Benzenoid
  • Heteroaromatic compound
  • Thiophene
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
PharmacodynamicsZileuton 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.
Mechanism of actionLeukotrienes 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.
Related Articles
AbsorptionRapidly and almost completely absorbed. The absolute bioavailability is unknown.
Volume of distribution
  • 1.2 L/kg
Protein binding93% bound to plasma proteins, primarily to albumin.
Metabolism

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

SubstrateEnzymesProduct
Zileuton
HydroxyzileutonDetails
Zileuton
Zileuton sulfoxideDetails
Zileuton
DehydroxyzyleutonDetails
Zileuton
Zileuton O-glucuronideDetails
Dehydroxyzyleuton
Dehydroxyzileuton sulfoxideDetails
Route of eliminationElimination 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.
Half life2.5 hours
Clearance
  • Apparent oral cl=7 mL/min/kg
ToxicityThe oral minimum lethal doses in mice and rats were 500-4000 and 300-1000 mg/kg in various preparations, respectively (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9915
Blood Brain Barrier+0.8846
Caco-2 permeable-0.5793
P-glycoprotein substrateNon-substrate0.6789
P-glycoprotein inhibitor INon-inhibitor0.9684
P-glycoprotein inhibitor IINon-inhibitor0.9765
Renal organic cation transporterNon-inhibitor0.9583
CYP450 2C9 substrateNon-substrate0.5907
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6384
CYP450 1A2 substrateInhibitor0.5318
CYP450 2C9 inhibitorNon-inhibitor0.7975
CYP450 2D6 inhibitorNon-inhibitor0.8866
CYP450 2C19 inhibitorNon-inhibitor0.6451
CYP450 3A4 inhibitorNon-inhibitor0.7062
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5821
Ames testAMES toxic0.5865
CarcinogenicityNon-carcinogens0.7968
BiodegradationNot ready biodegradable0.985
Rat acute toxicity2.2646 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9884
hERG inhibition (predictor II)Non-inhibitor0.9051
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Cornerstone therapeutics inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral600 mg/1
Tablet, multilayer, extended releaseoral600 mg/1
Prices
Unit descriptionCostUnit
Zyflo 600 mg tablet6.49USD tablet
Zyflo CR 600 mg 12 Hour tablet6.23USD tablet
Zyflo 600 mg filmtab5.99USD tablet
Zyflo cr 600 mg tablet5.99USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4873259 No1993-12-092010-12-09Us
US5422123 No1995-06-062012-06-06Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point144.2-145.2 °CNot Available
water solubilityPractically insoluble (0.5 mg/ml)Not Available
logP0.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0539 mg/mLALOGPS
logP2.01ALOGPS
logP2.01ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)8.84ChemAxon
pKa (Strongest Basic)-5.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area66.56 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity61.96 m3·mol-1ChemAxon
Polarizability24.14 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Emanuele ATTOLINA, Gianmaria Dell’Anna, Roberto Rossi, Pietro Allegrini, Gabriele Razzetti, “PROCESS FOR THE PREPARATION OF ZILEUTON.” U.S. Patent US20090286996, issued November 19, 2009.

US20090286996
General References
  1. Berger W, De Chandt MT, Cairns CB: Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract. 2007 Apr;61(4):663-76. [PubMed:17394438 ]
  2. Wenzel SE, Kamada AK: Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother. 1996 Jul-Aug;30(7-8):858-64. [PubMed:8826571 ]
  3. Malo PE, Bell RL, Shaughnessy TK, Summers JB, Brooks DW, Carter GW: The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis. Pulm Pharmacol. 1994 Apr;7(2):73-9. [PubMed:8081074 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (129 KB)
MSDSDownload (14.8 KB)
Interactions
Drug Interactions
Drug
LoxapineThe risk or severity of adverse effects can be increased when Zileuton is combined with Loxapine.
PimozideThe serum concentration of Pimozide can be increased when it is combined with Zileuton.
PropranololThe serum concentration of Propranolol can be increased when it is combined with Zileuton.
TheophyllineThe serum concentration of Theophylline can be increased when it is combined with Zileuton.
TizanidineThe serum concentration of Tizanidine can be increased when it is combined with Zileuton.
WarfarinThe serum concentration of Warfarin can be increased when it is combined with Zileuton.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Iron ion binding
Specific Function:
Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
Gene Name:
ALOX5
Uniprot ID:
P09917
Molecular Weight:
77982.595 Da
References
  1. Wenzel SE: Leukotriene receptor antagonists and related compounds. Can Respir J. 1999 Mar-Apr;6(2):189-93. [PubMed:10322101 ]
  2. Hardy DB, Pereria LE, Yang K: Prostaglandins and leukotriene B4 are potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells. Biol Reprod. 1999 Jul;61(1):40-5. [PubMed:10377029 ]
  3. Yamashita M, Kushihara M, Hirasawa N, Takasaki W, Takahagi H, Takayanagi M, Ohuchi K: Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells. Br J Pharmacol. 2000 Jan;129(2):367-73. [PubMed:10694244 ]
  4. Qian C, Hwang SB, Libertine-Garahan L, Eckman JB, Cai X, Scannell RT, Yeh CG: Anti-inflammatory activities of LDP-392, a dual PAF receptor antagonist and 5-lipoxygenase inhibitor. Pharmacol Res. 2001 Sep;44(3):213-20. [PubMed:11529688 ]
  5. Coffey MJ, Phare SM, Peters-Golden M: Peroxynitrite-induced nitrotyrosination of proteins is blocked by direct 5-lipoxygenase inhibitor zileuton. J Pharmacol Exp Ther. 2001 Oct;299(1):198-203. [PubMed:11561080 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Zouboulis CC: Zileuton, a new efficient and safe systemic anti-acne drug. Dermatoendocrinol. 2009 May;1(3):188-92. [PubMed:20436887 ]
  8. Zouboulis CC, Seltmann H, Alestas T: Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis. Exp Dermatol. 2010 Feb;19(2):148-50. doi: 10.1111/j.1600-0625.2009.00929.x. Epub 2009 Jul 23. [PubMed:19645854 ]
  9. Berger W, De Chandt MT, Cairns CB: Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract. 2007 Apr;61(4):663-76. [PubMed:17394438 ]
  10. Guidot DM, Repine MJ, Westcott JY, Repine JE: Intrinsic 5-lipoxygenase activity is required for neutrophil responsivity. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8156-9. [PubMed:8058773 ]
  11. Wenzel SE, Kamada AK: Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother. 1996 Jul-Aug;30(7-8):858-64. [PubMed:8826571 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [PubMed:19754423 ]
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]
  3. Machinist JM, Mayer MD, Shet MS, Ferrero JL, Rodrigues AD: Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193. Drug Metab Dispos. 1995 Oct;23(10):1163-74. [PubMed:8654206 ]
  4. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]
  2. Machinist JM, Mayer MD, Shet MS, Ferrero JL, Rodrigues AD: Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193. Drug Metab Dispos. 1995 Oct;23(10):1163-74. [PubMed:8654206 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the gener...
Gene Name:
PTGS1
Uniprot ID:
P23219
Molecular Weight:
68685.82 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Retinoic acid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A9
Uniprot ID:
O60656
Molecular Weight:
59940.495 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23