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Tiotropium

July 24, 2017
Common Name

Tiotropium Description

Tiotropium is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive plimonary disease (COPD). Tiotropium is a muscarinic receptor antagonist, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source Tiotropium bromideHMDB 679 BR, BAMeSH 7-((Hydroxybis(2-thienyl)acetyl)oxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo(3.3.1.0(2,4))nonane bromideMeSH BA679 BRMeSH BA 679 BRMeSH BA-679 BRMeSH SpirivaMeSH BR, BA 679MeSH Bromide, tiotropiumMeSH

Chemical Formlia

C19H22NO4S2 Average Molecliar Weight

392.512 Monoisotopic Molecliar Weight

392.099024577 IUPAC Name

(1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0²,⁴]nonan-9-ium Traditional Name

tiotropium CAS Registry Number

186691-13-4 SMILES

C[N+]1(C)[C@H]2CC(C[C@@H]1[C@@H]1O[C@H]21)OC(=O)C(O)(C1=CC=CS1)C1=CC=CS1

InChI Identifier

InChI=1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16+,17-

InChI Key

LERNTVKEWCAPOY-KYQOMENCSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as morpholines. These are organic compounds containing a morpholine moiety, which consists of a six-member aliphatic saturated ring with the formlia C4H9NO, where the oxygen and nitrogen atoms lie at positions 1 and 4, respectively. Kingdom

Chemical entities Super Class

Organic compounds Class

Organoheterocyclic compounds Sub Class

Oxazinanes Direct Parent

Morpholines Alternative Parents

  • Piperidines
  • N-alkylpyrrolidines
  • Thiophenes
  • Tetraalkylammonium salts
  • Tertiary alcohols
  • Heteroaromatic compounds
  • Carboxylic acid esters
  • Azacyclic compounds
  • Oxacyclic compounds
  • Dialkyl ethers
  • Epoxides
  • Monocarboxylic acids and derivatives
  • Organopnictogen compounds
  • Carbonyl compounds
  • Amines
  • Hydrocarbon derivatives
  • Aromatic alcohols
  • Organic salts
  • Organic oxides
  • Organic cations

    • Substituents

  • Morpholine
  • Piperidine
  • N-alkylpyrrolidine
  • Pyrrolidine
  • Tetraalkylammonium salt
  • Quaternary ammonium salt
  • Heteroaromatic compound
  • Tertiary alcohol
  • Thiophene
  • Carboxylic acid ester
  • Carboxylic acid derivative
  • Dialkyl ether
  • Oxirane
  • Ether
  • Monocarboxylic acid or derivatives
  • Oxacycle
  • Azacycle
  • Organopnictogen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Alcohol
  • Carbonyl group
  • Organic oxide
  • Hydrocarbon derivative
  • Organic nitrogen compound
  • Amine
  • Aromatic alcohol
  • Organic salt
  • Organic cation
  • Aromatic heteropolycyclic compound

    • Molecliar Framework

    Aromatic heteropolycyclic compounds External Descriptors

    Not Available Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Anticholinergic Agents
  • Bronchodilator Agents
  • Cholinergic Antagonists
  • Muscarinic Antagonists
  • Parasympatholytics

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility1.56e-02 g/LNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility0.016 mg/mLALOGPS logP-0.55ALOGPS logP-1.8ChemAxon logS-4.4ALOGPS pKa (Strongest Acidic)10.35ChemAxon pKa (Strongest Basic)-4.3ChemAxon Physiological Charge1ChemAxon Hydrogen Acceptor Count3ChemAxon Hydrogen Donor Count1ChemAxon Polar Surface Area59.06 Å2ChemAxon Rotatable Bond Count5ChemAxon Refractivity109.18 m3·mol-1ChemAxon Polarizability39.69 Å3ChemAxon Number of Rings5ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Not 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 DB01409

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01409

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB01409 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

    2343227 KEGG Compound ID

    Not Available BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Tiotropium NuGOwiki Link

    HMDB15479 Metagene Link

    HMDB15479 METLIN ID

    Not Available PubChem Compound

    3086655 PDB ID

    Not Available ChEBI ID

    Not Available

    Product: Nimorazole

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References Not Available

    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:
    Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
    Gene Name:
    CYP2D6
    Uniprot ID:
    P10635
    Molecular weight:
    55768.94
    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 G-protein coupled receptor protein signaling pathway
    Specific function:
    The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover
    Gene Name:
    CHRM3
    Uniprot ID:
    P20309
    Molecular weight:
    66127.4
    References
    1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
    2. Hansel TT, Barnes PJ: Tiotropium bromide: a novel once-daily anticholinergic bronchodilator for the treatment of COPD. Drugs Today (Barc). 2002 Sep;38(9):585-600. [PubMed:12582447 ]
    3. Barnes PJ: Tiotropium bromide. Expert Opin Investig Drugs. 2001 Apr;10(4):733-40. [PubMed:11281822 ]
    4. Barnes PJ, Belvisi MG, Mak JC, Haddad EB, OConnor B: Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci. 1995;56(11-12):853-9. [PubMed:10188785 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover
    Gene Name:
    CHRM1
    Uniprot ID:
    P11229
    Molecular weight:
    51420.4
    References
    1. Hansel TT, Barnes PJ: Tiotropium bromide: a novel once-daily anticholinergic bronchodilator for the treatment of COPD. Drugs Today (Barc). 2002 Sep;38(9):585-600. [PubMed:12582447 ]
    2. Barnes PJ: Tiotropium bromide. Expert Opin Investig Drugs. 2001 Apr;10(4):733-40. [PubMed:11281822 ]
    3. Barnes PJ, Belvisi MG, Mak JC, Haddad EB, OConnor B: Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci. 1995;56(11-12):853-9. [PubMed:10188785 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition
    Gene Name:
    CHRM2
    Uniprot ID:
    P08172
    Molecular weight:
    51714.6
    References
    1. Hansel TT, Barnes PJ: Tiotropium bromide: a novel once-daily anticholinergic bronchodilator for the treatment of COPD. Drugs Today (Barc). 2002 Sep;38(9):585-600. [PubMed:12582447 ]
    2. Barnes PJ, Belvisi MG, Mak JC, Haddad EB, OConnor B: Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci. 1995;56(11-12):853-9. [PubMed:10188785 ]

    Transporters

    General function:
    Involved in ion transmembrane transporter activity
    Specific function:
    Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3
    Gene Name:
    SLC22A5
    Uniprot ID:
    O76082
    Molecular weight:
    62751.1
    References
    1. Nakamura T, Nakanishi T, Haruta T, Shirasaka Y, Keogh JP, Tamai I: Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010 Feb 1;7(1):187-95. doi: 10.1021/mp900206j. [PubMed:20020740 ]
    General function:
    Involved in ion transmembrane transporter activity
    Specific function:
    Sodium-ion dependent, low affinity carnitine transporter. Probably transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 1.78. A key substrate of this transporter seems to be ergothioneine (ET)
    Gene Name:
    SLC22A4
    Uniprot ID:
    Q9H015
    Molecular weight:
    62154.5
    References
    1. Nakamura T, Nakanishi T, Haruta T, Shirasaka Y, Keogh JP, Tamai I: Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010 Feb 1;7(1):187-95. doi: 10.1021/mp900206j. [PubMed:20020740 ]

    PMID: 23921645

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