Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:28:01 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2938
Identification
Common NameFexofenadine
ClassSmall Molecule
DescriptionFexofenadine is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine, an antihistamine with potentially fatal contraindications. Fexofenadine, like other second-generation antihistamines, does not readily enter the brain from the blood, and so causes less drowsiness than first generation histamine receptor antagonists; Fexofenadine hydrochloride (brand names include Allegra and Telfast) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine, an antihistamine with potentially fatal contraindications. Fexofenadine, like other second generation antihistamines, does not readily enter the brain from the blood, and so causes less drowsiness than first-generation histamine-receptor antagonists.
Compound Type
  • Amine
  • Anti-Allergic Agent
  • Drug
  • Food Toxin
  • Histamine Antagonist
  • Histamine H1 Antagonist, Non-Sedating
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)butyl)-alpha,alpha-dimethylbenzeneacetic acid
Allegra
Carboxyterfenadine
Fastofen
Fexidine
Fexofenadine hydrochloride
Telfast
Terfenadine acid metabolite
Terfenadine carboxylate
Terfenadine-COOH
Vifas
Chemical FormulaC32H39NO4
Average Molecular Mass501.656 g/mol
Monoisotopic Mass501.288 g/mol
CAS Registry Number83799-24-0
IUPAC Name2-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic acid
Traditional Namefexofenadine
SMILESCC(C)(C(O)=O)C1=CC=C(C=C1)C(O)CCCN1CCC(CC1)C(O)(C1=CC=CC=C1)C1=CC=CC=C1
InChI IdentifierInChI=1/C32H39NO4/c1-31(2,30(35)36)25-17-15-24(16-18-25)29(34)14-9-21-33-22-19-28(20-23-33)32(37,26-10-5-3-6-11-26)27-12-7-4-8-13-27/h3-8,10-13,15-18,28-29,34,37H,9,14,19-23H2,1-2H3,(H,35,36)
InChI KeyInChIKey=RWTNPBWLLIMQHL-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as diphenylmethanes. Diphenylmethanes are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylmethanes
Direct ParentDiphenylmethanes
Alternative Parents
Substituents
  • Diphenylmethane
  • Phenylbutylamine
  • Phenylpropane
  • Aralkylamine
  • Piperidine
  • Tertiary alcohol
  • Amino acid or derivatives
  • Secondary alcohol
  • Amino acid
  • Tertiary amine
  • Tertiary aliphatic amine
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Organic nitrogen compound
  • Organic oxide
  • Amine
  • Carbonyl group
  • Aromatic alcohol
  • Alcohol
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Brain
  • Kidney
  • Liver
  • Skin
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point142.5°C
Boiling PointNot Available
SolubilitySlightly soluble
LogP5.6
Predicted Properties
PropertyValueSource
Water Solubility0.0027 g/LALOGPS
logP5.02ALOGPS
logP2.94ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)4.04ChemAxon
pKa (Strongest Basic)9.01ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area81 ŲChemAxon
Rotatable Bond Count10ChemAxon
Refractivity147.98 m³·mol⁻¹ChemAxon
Polarizability57.42 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-0912400000-d47ca5514638bcd48093View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-001i-1931153000-7fd2e3b3cc17ae068da6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a6r-0005900000-17ae091cc3d9ba9c62f3View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a6r-0396000000-be2d6fedab983b50c280View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4i-1970000000-c78b1c745afc54f58e01View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4r-0920000000-9ad3dc88e743866c23caView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0btj-0900000000-66a31911b29382b93745View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4i-1900000000-ce2d00bbddc284806cb0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0udi-0000090000-2622c1f2ddb4bff3f93dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0159-0000910000-0afa1079fbe9a822e35cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00xr-1920200000-1163d721ce08480aea71View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-1910000000-c593678096415da5efb2View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-002f-2900000000-01de1f32826ab5569301View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-002f-3900000000-72f624b2d6e05d29cb72View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0f89-0001930000-b9b7ff78564293a249b0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0541-0212900000-ab3069ba65212a7da302View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000g-1985500000-f990cf713f3191736f10View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0100690000-e140f2c9a1bcece115e3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0zj0-4223930000-8c8b81776964fc2cb368View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004u-9651000000-b823e5714fa6afb8f50fView in MoNA
Toxicity Profile
Route of ExposureOral. 33%
Mechanism of ToxicityLike other H1-blockers, Fexofenadine competes with free histamine for binding at H1-receptors in the GI tract, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Fexofenadine exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic or beta-adrenergic-receptor blocking effects.
MetabolismApproximately 5% of the total dose is metabolized, by cytochrome P450 3A4 and by intestinal microflora. Half Life: 14.4 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesAn antihistamine drug used in the treatment of hayfever and similar allergy symptoms.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects include dizziness, drowsiness, and dry mouth.
TreatmentIn the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. (12)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00950
HMDB IDHMDB05030
PubChem Compound ID3348
ChEMBL IDCHEMBL914
ChemSpider ID3231
KEGG IDC06999
UniProt IDNot Available
OMIM ID
ChEBI ID5050
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFexofenadine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFexofenadine
References
Synthesis Reference

Federico Milla, “Processes for the production of fexofenadine.” U.S. Patent US20030166682, issued September 04, 2003.

MSDSLink
General References
  1. Smith SM, Gums JG: Fexofenadine: biochemical, pharmacokinetic and pharmacodynamic properties and its unique role in allergic disorders. Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):813-22. doi: 10.1517/17425250903044967. [19545214 ]
  2. Bachert C: A review of the efficacy of desloratadine, fexofenadine, and levocetirizine in the treatment of nasal congestion in patients with allergic rhinitis. Clin Ther. 2009 May;31(5):921-44. doi: 10.1016/j.clinthera.2009.05.017. [19539095 ]
  3. Markham A, Wagstaff AJ: Fexofenadine. Drugs. 1998 Feb;55(2):269-74; discussion 275-6. [9506246 ]
  4. Golightly LK, Greos LS: Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Drugs. 2005;65(3):341-84. [15669879 ]
  5. Molimard M, Diquet B, Benedetti MS: Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol. 2004 Aug;18(4):399-411. [15312146 ]
  6. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB: OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos. 1999 Aug;27(8):866-71. [10421612 ]
  7. Simons FE, Silver NA, Gu X, Simons KJ: Clinical pharmacology of H1-antihistamines in the skin. J Allergy Clin Immunol. 2002 Nov;110(5):777-83. [12417888 ]
  8. Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, Funaki Y, Itoh M, Iwata R, Wong DF, Yanai K: Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol. 2004 Aug;44(8):890-900. [15286093 ]
  9. Purohit A, Duvernelle C, Melac M, Pauli G, Frossard N: Twenty-four hours of activity of cetirizine and fexofenadine in the skin. Ann Allergy Asthma Immunol. 2001 Apr;86(4):387-92. [11345280 ]
  10. Inoue T, Katoh N, Kishimoto S, Matsunaga K: Inhibitory effects of oral prednisolone and fexofenadine on skin responses by prick tests with histamine and compound 48/80. J Dermatol Sci. 2002 Dec;30(3):180-4. [12443840 ]
  11. Drugs.com [Link]
  12. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Histamine receptor activity
Specific Function:
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Gene Name:
HRH1
Uniprot ID:
P35367
Molecular Weight:
55783.61 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.01 uMNot AvailableBindingDB 22874
Inhibitory0.027 uMNot AvailableBindingDB 22874
IC500.078 uMNot AvailableBindingDB 22874
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, Funaki Y, Itoh M, Iwata R, Wong DF, Yanai K: Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol. 2004 Aug;44(8):890-900. [15286093 ]
  3. Cavero I, Mestre M, Guillon JM, Heuillet E, Roach AG: Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans? Drug Saf. 1999;21 Suppl 1:19-31; discussion 81-7. [10597865 ]
  4. Amon U, Amon S, Gibbs BF: In vitro studies with fexofenadine, a new nonsedating histamine H1 receptor antagonist, on isolated human basophils. Inflamm Res. 2000 Apr;49 Suppl 1:S13-4. [10864400 ]
  5. Abbas MN, Abdel Fattah AA, Zahran E: A novel membrane sensor for histamine H1-receptor antagonist "fexofenadine". Anal Sci. 2004 Aug;20(8):1137-42. [15352500 ]
  6. Grzelewska-Rzymowska I, Kroczynska-Bednarek J, Pietrzkowicz M: [Effect of fexofenadine--selective antagonist of histamine receptor (H1) on histamine-induced bronchoconstriction]. Pol Merkur Lekarski. 2003 Jan;14(79):43-6. [12712828 ]
  7. Kubota K, Kurebayashi H, Miyachi H, Tobe M, Onishi M, Isobe Y: Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H(1) antagonists. Bioorg Med Chem Lett. 2009 May 15;19(10):2766-71. doi: 10.1016/j.bmcl.2009.03.124. Epub 2009 Mar 28. [19362477 ]
  8. Kubota K, Kurebayashi H, Miyachi H, Tobe M, Onishi M, Isobe Y: Synthesis and structure-activity relationship of tricyclic carboxylic acids as novel anti-histamines. Bioorg Med Chem. 2011 May 1;19(9):3005-21. doi: 10.1016/j.bmc.2011.03.003. Epub 2011 Mar 11. [21470866 ]
  9. Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P: Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol. 2002 Feb;61(2):391-9. [11809864 ]
  10. Aslanian R, Piwinski JJ, Zhu X, Priestley T, Sorota S, Du XY, Zhang XS, McLeod RL, West RE, Williams SM, Hey JA: Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5043-7. doi: 10.1016/j.bmcl.2009.07.047. Epub 2009 Aug 5. [19660947 ]
  11. Triggiani M, Gentile M, Secondo A, Granata F, Oriente A, Taglialatela M, Annunziato L, Marone G: Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol. 2001 Mar 15;166(6):4083-91. [11238657 ]
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5021.37962 uMNot AvailableBindingDB 22874
IC5021.38 uMNot AvailableBindingDB 22874
IC5021.57 uMNot AvailableBindingDB 22874
IC5023 uMNot AvailableBindingDB 22874
IC5065 uMNot AvailableBindingDB 22874
IC50>0.1 uMNot AvailableBindingDB 22874
IC50>100 uMNot AvailableBindingDB 22874
References
  1. Ermondi G, Visentin S, Caron G: GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers. Eur J Med Chem. 2009 May;44(5):1926-32. doi: 10.1016/j.ejmech.2008.11.009. Epub 2008 Nov 28. [19110341 ]
  2. Rajamani R, Tounge BA, Li J, Reynolds CH: A two-state homology model of the hERG K+ channel: application to ligand binding. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1737-41. [15745831 ]
  3. Cavalli A, Poluzzi E, De Ponti F, Recanatini M: Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002 Aug 29;45(18):3844-53. [12190308 ]
  4. Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, Korolev AM, Lysenkova LN, Miroshnikova OV, Hendrix J, Rampe D: Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches. Bioorg Med Chem Lett. 2003 May 19;13(10):1829-35. [12729675 ]
  5. Zhu BY, Jia ZJ, Zhang P, Su T, Huang W, Goldman E, Tumas D, Kadambi V, Eddy P, Sinha U, Scarborough RM, Song Y: Inhibitory effect of carboxylic acid group on hERG binding. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5507-12. Epub 2006 Aug 22. [16931010 ]
  6. Mihalic JT, Fan P, Chen X, Chen X, Fu Y, Motani A, Liang L, Lindstrom M, Tang L, Chen JL, Jaen J, Dai K, Li L: Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3781-5. doi: 10.1016/j.bmcl.2012.04.006. Epub 2012 Apr 7. [22542010 ]
  7. Imai YN, Ryu S, Oiki S: Docking model of drug binding to the human ether-a-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach. J Med Chem. 2009 Mar 26;52(6):1630-8. doi: 10.1021/jm801236n. [19260734 ]
  8. Aslanian R, Piwinski JJ, Zhu X, Priestley T, Sorota S, Du XY, Zhang XS, McLeod RL, West RE, Williams SM, Hey JA: Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5043-7. doi: 10.1016/j.bmcl.2009.07.047. Epub 2009 Aug 5. [19660947 ]
General Function:
Histamine receptor activity
Specific Function:
The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist).
Gene Name:
HRH4
Uniprot ID:
Q9H3N8
Molecular Weight:
44495.375 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 22874
References
  1. Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R: Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther. 2005 Sep;314(3):1310-21. Epub 2005 Jun 9. [15947036 ]