1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea

• ChemBase ID: 624
• Molecular Formular: C11H12N2O2S
• Molecular Mass: 236.29018
• Monoisotopic Mass: 236.06194863
• SMILES: s1c(C(N(O)C(=O)N)C)cc2c1cccc2
• Canonical SMILES: ON(C(c1cc2c(s1)cccc2)C)C(=O)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)
• InChIKey: MWLSOWXNZPKENC-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea
• IUPAC Traditional name: zileuton; 1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea
• Brand Name: Leutrol; Zyflo; Zyflo CR
• Synonyms: Zileutonum [INN-Latin]; zileuton; Zileuton; 1-(1-(benzo[b]thiophen-2-yl)ethyl)-1-hydroxyurea; (±)-N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)urea; Zileuton; Zyflo CR; N-(1-Benzo[b]thien-2-yl-ethyl)-N-hydroxyurea; A-64077; Abbott 64077; Leutrol; ZYFLO

Database IDs

• CAS Number: 111406-87-2
• MDL Number: MFCD00866097
• PubChem SID: 160964087; 46506394
• PubChem CID: 60490

CALCULATED PROPERTIES

JChem

• Acid pKa: 8.837783
• H Acceptors: 2
• H Donor: 2
• LogD (pH = 5.5): 2.0059743
• LogD (pH = 7.4): 1.9906728
• Log P: 2.006173
• Molar Refractivity: 61.9595 cm^3
• Polarizability: 24.979395 Å^3
• Polar Surface Area: 66.56 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.01
• LOG S: -3.64
• Solubility (Water): 5.39e-02 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: ≥20 mg/mL at ~60 °C (warm up to 60 C for 5min); Practically insoluble (0.5 mg/ml)
• Apperance: White Solid; white to off-white powder
• Melting Point: 157-158°C
• Hydrophobicity(logP): 0.9

Safety Information

• Storage Condition: -20°C; Refrigerator
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 1
• Risk Statements: 22-36
• Safety Statements: 26
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H302-H319
• GHS Precautionary statements: P305 + P351 + P338
• Storage Temperature: room temp

Pharmacology Properties

• Target: 5-lipoxygenase(5-LO)
• Mechanism of Action: 5-Lipoxygenase (5-LOX) inhibitor; inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation; weak inhibitor of CYP 1A2

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Application(s): Antiallergic; Antiinflammatory agent; Investigated for treatment of irritable bowel disease; Potential antiasthmatic agent
• Empirical Formula (Hill Notation): C11H12N2O2S

DETAILS

DrugBank - DB00744

• Drug Groups: approved; investigational
• 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.
• Indication: For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
• Pharmacology: 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.
• 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
• Biotransformation: Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4.
• Absorption: Rapidly and almost completely absorbed. The absolute bioavailability is unknown.
• Half Life: 2.5 hours
• Protein Binding: 93% bound to plasma proteins, primarily to albumin.
• 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.
• Distribution: * 1.2 L/kg
• Clearance: * Apparent oral cl=7 mL/min/kg
• References: 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] ; 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] ; 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: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1443

Research Area: Chronic obstructive pulmonary disease,Acute asthma
Biological Activity:
Zileuton (ZYFLO) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Zileuton is used for the maintenance treatment of asthma. [1]

Sigma Aldrich - Z4277

Biochem/physiol Actions
Zileuton is an anti-asthmatic, an inhibitor of 5-lipoxygenase; the initial enzyme in the biosynthesis of leukotrienes from arachidonic acid.
Other Notes
Tandem Mass Spectrometry data independently generated by Scripps Center for Metabolomics is available to view or download in PDF. Z4277.pdf Tested metabolites are featured on Scripps Center for Metabolomics METLIN Metabolite Database. To learn more, visit sigma.com/metlin.

Toronto Research Chemicals - Z420000

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

REFERENCES

• 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
• 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
• 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
• http://en.wikipedia.org/wiki/Zileuton
• Carter, G.W., et al.: J. Pharmacol. Exp. Ther., 256, 929 (1991)
• Weinblatt, M.E., et al.: J. Rheumatol., 19, 1537 (1991)
• McGill, K and Busse, W.W.: Lancet, 348, 519 (1996)
• 1. 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
• 2. Lu P, Schrag ML, Slaughter DE, Raab CE, Shou M, Rodrigues AD. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor.
• Drug Metab Dispos. 2003 Nov;31(11):1352-60.