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Alosetron

July 24, 2017
Common Name

Alosetron Description

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modliate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source 2,3,4,5-tetrahydro-5-Methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-oneChEBI Alosetron HCLHMDB Alosetron monohydrochlorideMeSH LotronexMeSH Alosetron hydrochlorideMeSH 2,3,4,5-tetrahydro-5-Methyl-2-((5-methylimidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-one monohydrochlorideMeSH GlaxoSmithKline brand OF alosetron hydrochlorideMeSH

Chemical Formlia

C17H18N4O Average Molecliar Weight

294.351 Monoisotopic Molecliar Weight

294.148061218 IUPAC Name

5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H,2H,3H,4H,5H-pyrido[4,3-b]indol-1-one Traditional Name

alosetron CAS Registry Number

122852-42-0 SMILES

CN1C2=C(C3=CC=CC=C13)C(=O)N(CC1=C(C)NC=N1)CC2

InChI Identifier

InChI=1S/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19)

InChI Key

JSWZEAMFRNKZNL-UHFFFAOYSA-N Chemical Taxonomy Description

This compound belongs to the class of organic compounds known as n-alkylindoles. These are compounds containing an indole moiety that carries an alkyl chain at the 1-position. Kingdom

Organic compounds Super Class

Organoheterocyclic compounds Class

Indoles and derivatives Sub Class

N-alkylindoles Direct Parent

N-alkylindoles Alternative Parents

  • Indoles
  • N-methylpyrroles
  • Benzenoids
  • Vinylogous amides
  • Tertiary carboxylic acid amides
  • Imidazoles
  • Heteroaromatic compounds
  • Lactams
  • Azacyclic compounds
  • Organopnictogen compounds
  • Organooxygen compounds
  • Organonitrogen compounds
  • Organic oxides
  • Hydrocarbon derivatives

    • Substituents

  • N-alkylindole
  • Indole
  • N-methylpyrrole
  • Substituted pyrrole
  • Benzenoid
  • Imidazole
  • Heteroaromatic compound
  • Pyrrole
  • Vinylogous amide
  • Azole
  • Tertiary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Carboxylic acid derivative
  • Azacycle
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organic oxide
  • Aromatic heteropolycyclic compound

    • Molecliar Framework

    Aromatic heteropolycyclic compounds External Descriptors

  • imidazoles (CHEBI:253342 )
  • pyridoindole (CHEBI:253342 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Gastrointestinal Agents
  • Serotonin Antagonists

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility4.38e-01 g/LNot Available LogP2Not Available

    Predicted Properties

    Property Value Source Water Solubility0.44 mg/mLALOGPS logP1.85ALOGPS logP1.21ChemAxon logS-2.8ALOGPS pKa (Strongest Acidic)13.32ChemAxon pKa (Strongest Basic)6.81ChemAxon Physiological Charge0ChemAxon Hydrogen Acceptor Count2ChemAxon Hydrogen Donor Count1ChemAxon Polar Surface Area53.92 Å2ChemAxon Rotatable Bond Count2ChemAxon Refractivity86.41 m3·mol-1ChemAxon Polarizability32.52 Å3ChemAxon Number of Rings4ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key LC-MS/MS

    LC-MS/MS Spectrum – , positivesplash10-0udi-0390000000-3b813a9458d2bce7516fView in MoNA Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

    Biological Properties Cellliar Locations

  • Membrane

    • Biofluid Locations

  • Blood
  • Urine

    • Tissue Location

    Not Available Pathways

    Not Available Normal Concentrations

    Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00969

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00969

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB00969 DrugBank Metabolite ID

    Not Available Phenol Explorer Compound ID

    Not Available Phenol Explorer Metabolite ID

    Not Available FoodDB ID

    Not Available KNApSAcK ID

    Not Available Chemspider ID

    2015 KEGG Compound ID

    Not Available BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Alosetron NuGOwiki Link

    HMDB15104 Metagene Link

    HMDB15104 METLIN ID

    Not Available PubChem Compound

    2099 PDB ID

    Not Available ChEBI ID

    253342

    Product: TH-238A

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [PubMed:14596662 ]
    2. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [PubMed:11060667 ]
    3. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin Ther. 2008 May;30(5):884-901. doi: 10.1016/j.clinthera.2008.05.002. [PubMed:18555935 ]
    4. Lewis JH: Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol. 2010 Feb;4(1):13-29. doi: 10.1586/egh.09.72. [PubMed:20136586 ]
    5. Andresen V, Hollerbach S: Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome? Drug Saf. 2004;27(5):283-92. [PubMed:15061683 ]

    Enzymes

    General function:
    Involved in monooxygenase 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 xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
    Gene Name:
    CYP3A4
    Uniprot ID:
    P08684
    Molecular weight:
    57255.585
    References
    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
    General function:
    Involved in monooxygenase 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, phenytoin, tolbutamide and losartan.
    Gene Name:
    CYP2C9
    Uniprot ID:
    P11712
    Molecular weight:
    55627.365
    References
    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
    General function:
    Involved in monooxygenase activity
    Specific function:
    Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
    Gene Name:
    CYP2E1
    Uniprot ID:
    P05181
    Molecular weight:
    56848.42
    References
    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
    General function:
    Involved in monooxygenase 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. 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. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
    Gene Name:
    CYP1A2
    Uniprot ID:
    P05177
    Molecular weight:
    58406.915
    References
    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
    General function:
    Involved in extracellular ligand-gated ion channel activity
    Specific function:
    This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel
    Gene Name:
    HTR3A
    Uniprot ID:
    P46098
    Molecular weight:
    55279.8
    References
    1. Clayton NM, Sargent R, Butler A, Gale J, Maxwell MP, Hunt AA, Barrett VJ, Cambridge D, Bountra C, Humphrey PP: The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat. Neurogastroenterol Motil. 1999 Jun;11(3):207-17. [PubMed:10354345 ]
    2. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [PubMed:14596662 ]
    3. Coldwell JR, Phillis BD, Sutherland K, Howarth GS, Blackshaw LA: Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery. J Physiol. 2007 Feb 15;579(Pt 1):203-13. Epub 2006 Nov 30. [PubMed:17138606 ]
    4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
    5. Houghton LA, Foster JM, Whorwell PJ: Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2000 Jun;14(6):775-82. [PubMed:10848662 ]
    6. Gunput MD: Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther. 1999 May;13 Suppl 2:70-6. [PubMed:10429744 ]
    7. Balfour JA, Goa KL, Perry CM: Alosetron. Drugs. 2000 Mar;59(3):511-8; discussion 519-20. [PubMed:10776833 ]
    8. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [PubMed:11060667 ]
    9. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin Ther. 2008 May;30(5):884-901. doi: 10.1016/j.clinthera.2008.05.002. [PubMed:18555935 ]
    10. Lewis JH: Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol. 2010 Feb;4(1):13-29. doi: 10.1586/egh.09.72. [PubMed:20136586 ]
    11. Andresen V, Hollerbach S: Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome? Drug Saf. 2004;27(5):283-92. [PubMed:15061683 ]

    PMID: 10037770

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