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Fosaprepitant

July 24, 2017
Common Name

Fosaprepitant Description

Fosaprepitant is only found in individuals that have used or taken this drug. It is an intravenously administered antiemetic drug. It is a prodrug of Aprepitant. It aids in the prevention of acute and delayed nausea and vomiting associated with chemotherapy treatment.Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis.In summary, the active form of fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source FosaprepitantumChEBI L-758,298ChEBI L-758298ChEBI Emend for injectionMeSH Fosaprepitant dimeglumineMeSH

Chemical Formlia

C23H22F7N4O6P Average Molecliar Weight

614.4066 Monoisotopic Molecliar Weight

614.116518403 IUPAC Name

(3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonic acid Traditional Name

fosaprepitant CAS Registry Number

172673-20-0 SMILES

C[C@@H](O[C@H]1OCCN(CC2=NC(=O)N(N2)P(O)(O)=O)[C@H]1C1=CC=C(F)C=C1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F

InChI Identifier

InChI=1S/C23H22F7N4O6P/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)40-20-19(13-2-4-17(24)5-3-13)33(6-7-39-20)11-18-31-21(35)34(32-18)41(36,37)38/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H,31,32,35)(H2,36,37,38)/t12-,19+,20-/m1/s1

InChI Key

BARDROPHSZEBKC-OITMNORJSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as phenylmorpholines. These are aromatic compounds containing a morpholine ring and a benzene ring linked to each other through a CC or a CN bond. Kingdom

Chemical entities Super Class

Organic compounds Class

Organoheterocyclic compounds Sub Class

Oxazinanes Direct Parent

Phenylmorpholines Alternative Parents

  • Trifluoromethylbenzenes
  • Fluorobenzenes
  • Aralkylamines
  • Aryl fluorides
  • Triazoles
  • Heteroaromatic compounds
  • Trialkylamines
  • Oxacyclic compounds
  • Azacyclic compounds
  • Acetals
  • Organopnictogen compounds
  • Organofluorides
  • Organic oxides
  • Hydrocarbon derivatives
  • Alkyl fluorides

    • Substituents

  • Phenylmorpholine
  • Trifluoromethylbenzene
  • Fluorobenzene
  • Halobenzene
  • Aralkylamine
  • Aryl fluoride
  • Aryl halide
  • Monocyclic benzene moiety
  • Benzenoid
  • Azole
  • Heteroaromatic compound
  • 1,2,4-triazole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Oxacycle
  • Acetal
  • Alkyl fluoride
  • Organofluoride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Amine
  • Alkyl halide
  • Organooxygen compound
  • Aromatic heteromonocyclic compound

    • Molecliar Framework

    Aromatic heteromonocyclic compounds External Descriptors

  • morpholines (CHEBI:64321 )
  • triazoles (CHEBI:64321 )
  • phosphoramide (CHEBI:64321 )
  • (trifluoromethyl)benzenes (CHEBI:64321 )
  • cyclic acetal (CHEBI:64321 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Antiemetics

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water SolubilityNot AvailableNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility0.0063 mg/mLALOGPS logP2.89ALOGPS logP2.4ChemAxon logS-5ALOGPS pKa (Strongest Acidic)1.02ChemAxon pKa (Strongest Basic)5.69ChemAxon Physiological Charge-2ChemAxon Hydrogen Acceptor Count9ChemAxon Hydrogen Donor Count3ChemAxon Polar Surface Area123.93 Å2ChemAxon Rotatable Bond Count9ChemAxon Refractivity138.63 m3·mol-1ChemAxon Polarizability49.92 Å3ChemAxon Number of Rings4ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key 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 DB06717

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06717

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB06717 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

    189912 KEGG Compound ID

    Not Available BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Fosaprepitant NuGOwiki Link

    HMDB15662 Metagene Link

    HMDB15662 METLIN ID

    Not Available PubChem Compound

    219090 PDB ID

    Not Available ChEBI ID

    64321

    Product: RO4987656

    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. Navari RM: Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther. 2008 Nov;8(11):1733-42. doi: 10.1586/14737140.8.11.1733. [PubMed:18983233 ]
    2. Sanchez RI, Wang RW, Newton DJ, Bakhtiar R, Lu P, Chiu SH, Evans DC, Huskey SE: Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos. 2004 Nov;32(11):1287-92. Epub 2004 Aug 10. [PubMed:15304427 ]
    General function:
    Involved in monooxygenase activity
    Specific function:
    Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
    Gene Name:
    CYP2C19
    Uniprot ID:
    P33261
    Molecular weight:
    55944.565
    References
    1. Navari RM: Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther. 2008 Nov;8(11):1733-42. doi: 10.1586/14737140.8.11.1733. [PubMed:18983233 ]
    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. Navari RM: Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther. 2008 Nov;8(11):1733-42. doi: 10.1586/14737140.8.11.1733. [PubMed:18983233 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is:substance P > substance K > neuromedin-K
    Gene Name:
    TACR1
    Uniprot ID:
    P25103
    Molecular weight:
    46250.5
    References
    1. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003 Jun 15;97(12):3090-8. [PubMed:12784346 ]
    2. Zhao MM, McNamara JM, Ho GJ, Emerson KM, Song ZJ, Tschaen DM, Brands KM, Dolling UH, Grabowski EJ, Reider PJ, Cottrell IF, Ashwood MS, Bishop BC: Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. J Org Chem. 2002 Sep 20;67(19):6743-7. [PubMed:12227806 ]
    3. Bergstrom M, Hargreaves RJ, Burns HD, Goldberg MR, Sciberras D, Reines SA, Petty KJ, Ogren M, Antoni G, Langstrom B, Eskola O, Scheinin M, Solin O, Majumdar AK, Constanzer ML, Battisti WP, Bradstreet TE, Gargano C, Hietala J: Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004 May 15;55(10):1007-12. [PubMed:15121485 ]
    4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

    PMID: 23902761

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