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Identification
Name Zileuton
Accession Number DB00744 (APRD00265)
Type small molecule
Groups approved
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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Zileutonum [INN-Latin]
Synonyms
Zileutonum [INN-Latin]
Salts Not Available
Brand names
Name Company
Leutrol
Zyflo
Zyflo CR
Brand mixtures Not Available
Categories
  • Lipoxygenase Inhibitors
  • Leukotriene Antagonists
CAS number 111406-87-2
Weight Average: 236.29
Monoisotopic: 236.061948328
Chemical Formula C11H12N2O2S
InChI Key InChIKey=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)
Plain Text
IUPAC Name
1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea
SMILES
CC(N(O)C(N)=O)C1=CC2=CC=CC=C2S1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzothiophenes
Substructures
  • Hydroxy Compounds
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Carbamates and Derivatives
  • Benzothiophenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Thiophenes
  • Hydroxylamines and Derivatives
Pharmacology
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.
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.
Absorption Rapidly and almost completely absorbed. The absolute bioavailability is unknown.
Volume of distribution
  • 1.2 L/kg
Protein binding 93% 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.
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.
Half life 2.5 hours
Clearance
  • Apparent oral cl=7 mL/min/kg
Toxicity The 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Cornerstone therapeutics inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Zyflo 600 mg tablet 6.49 USD tablet
Zyflo CR 600 mg 12 Hour tablet 6.23 USD tablet
Zyflo 600 mg filmtab 5.99 USD tablet
Zyflo cr 600 mg tablet 5.99 USD tablet
Patents
Country Patent Number Approved Expires (estimated)
United States 5422123 1995-06-06 2012-06-06
United States 4873259 1993-12-09 2010-12-09
Properties
State solid
Melting point 144.2-145.2 oC
Experimental Properties
Property Value Source
water solubility Practically insoluble (0.5 mg/ml) PhysProp
logP 0.9 PhysProp
Predicted Properties
Property Value Source
water solubility 5.39e-02 g/l ALOGPS
logP 2.01 ALOGPS
logP 2.01 ChemAxon Molconvert
logS -3.6 ALOGPS
pKa 0 ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 66.56 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 61.96 ChemAxon Molconvert
polarizability 24.14 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  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
  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
  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
External Links
Resource Link
KEGG Drug D00414 Link_out
PubChem Compound 60490 Link_out
PubChem Substance 46506394 Link_out
ChemSpider 54531 Link_out
ChEBI 10112 Link_out
ChEMBL 10112 Link_out
Therapeutic Targets Database DAP000591 Link_out
PharmGKB PA451955 Link_out
RxList http://www.rxlist.com/cgi/generic/zileuton.htm Link_out
Drugs.com http://www.drugs.com/cdi/zileuton.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Zileuton Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (129 KB)
MSDS show (14.8 KB)
Interactions
Drug Interactions
Drug Interaction
Aminophylline Zileuton increases the effect and toxicity of theophylline
Dihydroergotamine Possible ergotism and severe ischemia with this combination
Ergotamine Possible ergotism and severe ischemia with this combination
Oxtriphylline Zileuton increases the effect and toxicity of theophylline
Pimozide Increased risk of cardiotoxicity and arrhythmias
Ramelteon Zileuton increases levels/toxicity of ramelteon
Theophylline Zileuton may increase the therapeutic and adverse effects of theophylline by increasing its serum concentration. Monitor for changes in the therapeutic and adverse effects of theophylline if zileuton is initiated, discontinued or dose changed. Dose alterations should be considered.
Food Interactions Not Available
Targets

1. Arachidonate 5-lipoxygenase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P09917 Link_out
Gene: ALOX5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wenzel SE: Leukotriene receptor antagonists and related compounds. Can Respir J. 1999 Mar-Apr;6(2):189-93. Pubmed
  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
  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
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Zouboulis CC: Zileuton, a new efficient and safe systemic anti-acne drug. Dermatoendocrinol. 2009 May;1(3):188-92. Pubmed
  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. Epub 2009 Jul 23. Pubmed
  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
  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
  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
Enzymes

1. Cytochrome P450 2C9

Actions: substrate

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, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Cytochrome P450 1A2

Actions: substrate, inhibitor

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 N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. 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
  4. 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

3. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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

4. Prostaglandin G/H synthase 1

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

5. UDP-glucuronosyltransferase 1-9

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols

UniProt ID: O60656 Link_out
Gene: UGT1A9 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:43