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Record Information
Version3.6
Creation Date2012-09-06 15:16:50 UTC
Update Date2017-03-02 21:33:27 UTC
HMDB IDHMDB14775
Secondary Accession NumbersNone
Metabolite Identification
Common NameAstemizole
DescriptionAstemizole is a long-acting, non-sedating second generation antihistamine used in the treatment of allergy symptoms. It was withdrawn from market by the manufacturer in 1999 due to the potential to cause arrhythmias at high doses, especially when when taken with CYP inhibitors or grapefruit juice.
Structure
Thumb
Synonyms
ValueSource
1-(P-Fluorobenzyl)-2-((1-(2-(P-methoxyphenyl)ethyl)piperid-4-yl)amino)benzimidazoleChEBI
1-(P-Fluorobenzyl)-2-((1-(P-methoxyphenethyl)-4-piperidyl)amino)benzimidazoleChEBI
AstemisonChEBI
AstemizolChEBI
AstemizolumChEBI
Alonga brand OF astemizoleMeSH
Astemizole alacan brandMeSH
Astemizole byk brandMeSH
Astemizole diba brandMeSH
Astemizole esteve brandMeSH
Astemizole senosiain brandMeSH
Astemizole ratiopharm brandMeSH
Esteve brand OF astemizoleMeSH
Fustery brand OF astemizoleMeSH
HistaminosMeSH
ICN brand OF astemizoleMeSH
RifedotMeSH
RimbolMeSH
Senosiain brand OF astemizoleMeSH
Smaller brand OF astemizoleMeSH
Alonga, astemizolMeSH
AsteminaMeSH
Astemizol alongaMeSH
Astemizole icn brandMeSH
Astemizole medinsa brandMeSH
Astemizole merck brandMeSH
Astemizole smaller brandMeSH
Astemizole urbion brandMeSH
Astemizole vita brandMeSH
AstesenMeSH
HubermizolMeSH
LaridalMeSH
Lesvi brand OF astemizoleMeSH
Reig jofre brand OF astemizoleMeSH
RomadinMeSH
Urbion brand OF astemizoleMeSH
Ratiopharm brand OF astemizoleMeSH
Ratiopharm, astemizolMeSH
Astemizole alonga brandMeSH
Astemizole elfar brandMeSH
Astemizole fustery brandMeSH
Astemizole janssen brandMeSH
Astemizole lesvi brandMeSH
Astemizole mcneil brandMeSH
Astemizole septa brandMeSH
Byk brand OF astemizoleMeSH
Diba brand OF astemizoleMeSH
Elfar brand OF astemizoleMeSH
EmdarMeSH
FustermizolMeSH
McNeil brand OF astemizoleMeSH
Merck brand OF astemizoleMeSH
SimproxMeSH
UrdrimMeSH
Alacan brand OF astemizoleMeSH
AlermizolMeSH
Astemizol ratiopharmMeSH
EsmacenMeSH
HismanalMeSH
Janssen brand OF astemizoleMeSH
Medinsa brand OF astemizoleMeSH
ParalerginMeSH
RetolenMeSH
Septa brand OF astemizoleMeSH
Vita brand OF astemizoleMeSH
Chemical FormulaC28H31FN4O
Average Molecular Weight458.5703
Monoisotopic Molecular Weight458.248189839
IUPAC Name1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-1,3-benzodiazol-2-amine
Traditional Nameastemizole
CAS Registry Number68844-77-9
SMILES
COC1=CC=C(CCN2CCC(CC2)NC2=NC3=CC=CC=C3N2CC2=CC=C(F)C=C2)C=C1
InChI Identifier
InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31)
InChI KeyGXDALQBWZGODGZ-UHFFFAOYSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganoheterocyclic compounds
Sub ClassBenzimidazoles
Direct ParentBenzimidazoles
Alternative Parents
Substituents
  • Benzimidazole
  • Phenethylamine
  • Anisole
  • Phenoxy compound
  • Phenol ether
  • Methoxybenzene
  • Alkyl aryl ether
  • Fluorobenzene
  • Halobenzene
  • Aralkylamine
  • Piperidine
  • Benzenoid
  • Aryl fluoride
  • Aryl halide
  • N-substituted imidazole
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Azole
  • Imidazole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Ether
  • Hydrocarbon derivative
  • Amine
  • Organic oxygen compound
  • Organic nitrogen compound
  • Organohalogen compound
  • Organofluoride
  • Organonitrogen compound
  • Organooxygen compound
  • Organopnictogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
StatusExpected but not Quantified
Origin
  • Drug
Biofunction
  • Anti-Allergic Agents
  • Antihistamines
  • Histamine H1 Antagonists, Non-Sedating
Application
  • Pharmaceutical
Cellular locations
  • Membrane
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point149.1 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility1.20e-03 g/LNot Available
LogP5.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0012 mg/mLALOGPS
logP5.92ALOGPS
logP5.39ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)8.75ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.32 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity135.64 m3·mol-1ChemAxon
Polarizability52.08 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Biological Properties
Cellular Locations
  • Membrane
Biofluid Locations
  • Blood
  • Urine
Tissue LocationNot Available
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00637
  • Not Applicable
details
UrineExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00637
  • Not Applicable
details
Abnormal Concentrations
Not Available
Predicted Concentrations
BiofluidValueOriginal ageOriginal sexOriginal conditionComments
Blood0-2 uMAdult (>18 years old)BothNormalPredicted based on drug qualities
Blood0-1 umol/mmol creatinineAdult (>18 years old)BothNormalPredicted based on drug qualities
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00637
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID2160
KEGG Compound IDC06832
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkAstemizole
NuGOwiki LinkHMDB14775
Metagene LinkHMDB14775
METLIN IDNot Available
PubChem Compound2247
PDB IDNot Available
ChEBI ID2896
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Wang X, Hockerman GH, Green HW 3rd, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL: Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway. FASEB J. 2006 Jul;20(9):1531-3. Epub 2006 May 24. [PubMed:16723379 ]
  2. Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ Jr: A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol. 2006 Aug;2(8):415-6. Epub 2006 Jul 2. [PubMed:16816845 ]

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. Nicolas JM, Whomsley R, Collart P, Roba J: In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines. Chem Biol Interact. 1999 Nov 15;123(1):63-79. [PubMed:10597902 ]
  2. Matsumoto S, Yamazoe Y: Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine. Br J Clin Pharmacol. 2001 Feb;51(2):133-42. [PubMed:11259984 ]
  3. Cvetkovic RS, Goa KL: Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802. [PubMed:12662125 ]
  4. Goto A, Adachi Y, Inaba A, Nakajima H, Kobayashi H, Sakai K: Identification of human p450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its inhibitory effect on enzyme activity. Biol Pharm Bull. 2004 May;27(5):684-90. [PubMed:15133245 ]
  5. Goto A, Ueda K, Inaba A, Nakajima H, Kobayashi H, Sakai K: Identification of human P450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its kinetic parameters and inhibition constants. Biol Pharm Bull. 2005 Feb;28(2):328-34. [PubMed:15684493 ]
  6. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
  7. 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 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.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular weight:
57108.065
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.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Molecular weight:
57525.03
General function:
Involved in monooxygenase activity
Specific function:
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible for the epoxidation of endogenous cardiac arachidonic acid pools.
Gene Name:
CYP2J2
Uniprot ID:
P51589
Molecular weight:
57610.165
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 ion channel activity
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). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular weight:
126653.5
References
  1. Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT: Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol. 1999 Jun;10(6):836-43. [PubMed:10376921 ]
  2. Chachin M, Katayama Y, Yamada M, Horio Y, Ohmura T, Kitagawa H, Uchida S, Kurachi Y: Epinastine, a nonsedating histamine H1 receptor antagonist, has a negligible effect on HERG channel. Eur J Pharmacol. 1999 Jun 25;374(3):457-60. [PubMed:10422790 ]
  3. Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G, Annunziato L: Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin Exp Allergy. 1999 Jul;29 Suppl 3:182-9. [PubMed:10444235 ]
  4. Grzelewska-Rzymowska I, Pietrzkowicz M, Gorska M: [The effect of second generation histamine antagonists on the heart]. Pneumonol Alergol Pol. 2001;69(3-4):217-26. [PubMed:11575008 ]
  5. Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin A, Cheng FC, Crumb WJ, Mitchell R: Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J Pharmacol Sci. 2004 Jul;95(3):311-9. [PubMed:15272206 ]
General function:
Involved in G-protein coupled receptor protein signaling pathway
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:
55783.6
References
  1. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF 3rd, Guinosso PJ Jr, Lynch JJ Jr: Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circ Res. 1995 Jan;76(1):110-9. [PubMed:8001268 ]
  2. Howarth PH, Emanuel MB, Holgate ST: Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels. Br J Clin Pharmacol. 1984 Jul;18(1):1-8. [PubMed:6146346 ]
  3. Kaliner MA, Check WA: Non-sedating antihistamines. Allergy Proc. 1988 Nov-Dec;9(6):649-63. [PubMed:3147222 ]
  4. 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. [PubMed:10597865 ]
  5. Llenas J, Cardelus I, Heredia A, de Mora F, Gristwood RW: Cardiotoxicity of histamine and the possible role of histamine in the arrhythmogenesis produced by certain antihistamines. Drug Saf. 1999;21 Suppl 1:33-8; discussion 81-7. [PubMed:10597866 ]
  6. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS: Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1984 Jul;28(1):38-61. [PubMed:6204835 ]
  7. Krstenansky PM, Cluxton RJ Jr: Astemizole: a long-acting, nonsedating antihistamine. Drug Intell Clin Pharm. 1987 Dec;21(12):947-53. [PubMed:2892659 ]
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Transporters

General function:
Involved in ATP binding
Specific function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular weight:
141477.3
References
  1. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [PubMed:12699389 ]
  2. Ishikawa M, Fujita R, Takayanagi M, Takayanagi Y, Sasaki K: Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole. Biol Pharm Bull. 2000 Jan;23(1):112-5. [PubMed:10706423 ]