Azelastine (T3D4558)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (7)XML
Targets (7)
Record Information
Version2.0
Creation Date2014-08-30 21:04:10 UTC
Update Date2014-12-24 20:26:52 UTC
Accession NumberT3D4558
Identification
Common NameAzelastine
ClassSmall Molecule
DescriptionAzelastine, a phthalazine derivative, is an antihistamine and mast cell stabilizer available as a nasal spray for hay fever and as eye drops for allergic conjunctivitis. Azelastine is also available as a combination product of azelastine hydrochloride and fluticasone propionate called Dymista®. Dymista® is indicated in patient over 12 years old for symptomatic relief of seasonal allergic rhinitis.
Compound Type
  • Amine
  • Anti-Allergic Agent
  • Bronchodilator Agent
  • Drug
  • Histamine H1 Antagonist, Non-Sedating
  • Lipoxygenase Inhibitor
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
4-(P-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone
Astelin
Astepro
Azelastina
Azelastinum
Optivar
Chemical FormulaC22H24ClN3O
Average Molecular Mass381.898 g/mol
Monoisotopic Mass381.161 g/mol
CAS Registry Number58581-89-8
IUPAC Name4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)-1,2-dihydrophthalazin-1-one
Traditional Nameazelastine
SMILESCN1CCCC(CC1)N1N=C(CC2=CC=C(Cl)C=C2)C2=CC=CC=C2C1=O
InChI IdentifierInChI=1/C22H24ClN3O/c1-25-13-4-5-18(12-14-25)26-22(27)20-7-3-2-6-19(20)21(24-26)15-16-8-10-17(23)11-9-16/h2-3,6-11,18H,4-5,12-15H2,1H3
InChI KeyInChIKey=MBUVEWMHONZEQD-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phthalazinones. Phthalazinones are compounds containing a phthalazine bearing a ketone group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazanaphthalenes
Sub ClassBenzodiazines
Direct ParentPhthalazinones
Alternative Parents
Substituents
  • Phthalazinone
  • Azepane
  • Chlorobenzene
  • Halobenzene
  • Pyridazinone
  • Monocyclic benzene moiety
  • Aryl chloride
  • Pyridazine
  • Aryl halide
  • Benzenoid
  • Heteroaromatic compound
  • Lactam
  • Tertiary amine
  • Tertiary aliphatic amine
  • Azacycle
  • Hydrocarbon derivative
  • Organic oxide
  • Organic nitrogen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Organopnictogen compound
  • Organic oxygen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point225 °C (hydrochloride salt)
Boiling PointNot Available
SolubilitySparingly soluble (hydrochloride salt)
LogP4.9
Predicted Properties
PropertyValueSource
Water Solubility0.0092 g/LALOGPS
logP3.81ALOGPS
logP4.04ChemAxon
logS-4.6ALOGPS
pKa (Strongest Basic)8.88ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.91 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity110.52 m³·mol⁻¹ChemAxon
Polarizability41.54 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03di-9886000000-488eee761663db10fdf72017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-001i-0219000000-689aed0dccf673820d4e2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03e9-2908000000-3d19ebb91515adce237b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-03e9-1908000000-95d1d10eb0ad7e0a5caa2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-00di-0593000000-58523cbdb28285c913e42021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-05i0-0940000000-8644fd48c2a4a3af1ceb2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-05i0-0950000000-344a725e5180781636512021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Positivesplash10-001i-0009000000-47ec9bd1fd4efec1a3932021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-001i-1349000000-8e49a62427e3060b124f2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-001i-0009000000-66d30432d2e83b7bef0b2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-001i-0129000000-f11386dc3536cefda9782021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0019000000-3cb870845555c5786c732016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-053r-0369000000-b74e000f63bb368b99b12016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03l0-9410000000-7199ebf04c51eb076d6c2016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0019000000-9890b690027006b28ee12016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-1159000000-752e6f7ffd2b5aeeca782016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-014i-1190000000-e1fac913b1bac22471392016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0009000000-65debeb41831c291eceb2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-0209000000-d6632dfc2bb4c411543c2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03fr-3942000000-125e45b36545578394a02021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0009000000-e093c6464a3534f2d4482021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0019000000-d58a8236055ebf7fd0e32021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-05o0-6963000000-f9e3f6b0ea6656234db42021-10-11View Spectrum
Toxicity Profile
Route of ExposureAbsorption of azelastine following ocular administration was relatively low. Systemic bioavailability is approximately 40% after nasal administration.
Mechanism of ToxicityAzelastine competes with histamine for the H1-receptor sites on effector cells and acts as an antagonist by inhibiting the release of histamine and other mediators involved in the allergic response.
MetabolismAzelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system, however the exact cytochrome P450 isoenzyme involved has not been determined. The major metabolite, desmethylazelastine, also has H1-receptor antagonist activity. Route of Elimination: Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system. Half Life: Elimination half-life (based on intravenous and oral administration) is 22 hours. Elimination half-life of the active metabolite, desmethylazelastine, is 54 hours (after oral administration of azelastine).
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the symptomatic treatment of seasonal allergic rhinitis and non-allergic rhinitis, as well as symptomatic relief of ocular itching associated with allergic conjunctivitis.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00972
HMDB IDNot Available
PubChem Compound ID2267
ChEMBL IDCHEMBL639
ChemSpider ID2180
KEGG IDC07768
UniProt IDNot Available
OMIM ID
ChEBI ID2950
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkAzelastine
References
Synthesis Reference

Yutaka Morita, Noritoshi Koyama, Shigemitsu Ohsawa, “Methods employing stable preparation containing azelastine hydrochloride.” U.S. Patent US6117864, issued December, 1990.

MSDST3D4558.pdf
General References
  1. Horak F: Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis. Ther Clin Risk Manag. 2008 Oct;4(5):1009-22. [19209282 ]
  2. Bernstein JA: Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin. 2007 Oct;23(10):2441-52. [17723160 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Histamine H1 receptor
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
Inhibitory0.0012 uMNot AvailableBindingDB 50341448
Inhibitory0.00126 uMNot AvailableBindingDB 50341448
Dissociation0.0002 uMNot AvailableBindingDB 50341448
References
  1. Casale TB: The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989 Apr;83(4):771-6. [2540229 ]
  2. Conde Hernandez DJ, Palma Aqilar JL, Delgado Romero J: Comparison of azelastine nasal spray and oral ebastine in treating seasonal allergic rhinitis. Curr Med Res Opin. 1995;13(6):299-304. [8829888 ]
  3. Antepara I, Jauregui I, Basomba A, Cadahia A, Feo F, Garcia JJ, Gonzalo MA, Luna I, Rubio M, Vazquez M: [Investigation of the efficacy and tolerability of azelastine nasal spray versus ebastine tablets in patients with seasonal allergic rhinitis]. Allergol Immunopathol (Madr). 1998 Jan-Feb;26(1):9-16. [9585822 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  5. Horak F: Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis. Ther Clin Risk Manag. 2008 Oct;4(5):1009-22. [19209282 ]
  6. Bernstein JA: Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin. 2007 Oct;23(10):2441-52. [17723160 ]
  7. Golden SJ, Craig TJ: Efficacy and safety of azelastine nasal spray for the treatment of allergic rhinitis. J Am Osteopath Assoc. 1999 Jul;99(7 Suppl):S7-12. [10478514 ]
  8. Procopiou PA, Browning C, Buckley JM, Clark KL, Fechner L, Gore PM, Hancock AP, Hodgson ST, Holmes DS, Kranz M, Looker BE, Morriss KM, Parton DL, Russell LJ, Slack RJ, Sollis SL, Vile S, Watts CJ: The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis. J Med Chem. 2011 Apr 14;54(7):2183-95. doi: 10.1021/jm1013874. Epub 2011 Mar 7. [21381763 ]
  9. Procopiou PA, Browning C, Gore PM, Lynn SM, Richards SA, Slack RJ, Sollis SL: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists. Bioorg Med Chem. 2012 Oct 15;20(20):6097-108. doi: 10.1016/j.bmc.2012.08.032. Epub 2012 Aug 31. [22985961 ]
Target Details
2. Potassium voltage-gated channel subfamily H member 2
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
IC500.1 uMNot AvailableBindingDB 50341448
References
  1. Procopiou PA, Browning C, Buckley JM, Clark KL, Fechner L, Gore PM, Hancock AP, Hodgson ST, Holmes DS, Kranz M, Looker BE, Morriss KM, Parton DL, Russell LJ, Slack RJ, Sollis SL, Vile S, Watts CJ: The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis. J Med Chem. 2011 Apr 14;54(7):2183-95. doi: 10.1021/jm1013874. Epub 2011 Mar 7. [21381763 ]
  2. Procopiou PA, Browning C, Gore PM, Lynn SM, Richards SA, Slack RJ, Sollis SL: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists. Bioorg Med Chem. 2012 Oct 15;20(20):6097-108. doi: 10.1016/j.bmc.2012.08.032. Epub 2012 Aug 31. [22985961 ]
Target Details
3. Alpha-1A adrenergic receptor
General Function:
Protein heterodimerization activity
Specific Function:
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:
ADRA1A
Uniprot ID:
P35348
Molecular Weight:
51486.005 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.05012 uMNot AvailableBindingDB 50341448
References
  1. Procopiou PA, Browning C, Gore PM, Lynn SM, Richards SA, Slack RJ, Sollis SL: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists. Bioorg Med Chem. 2012 Oct 15;20(20):6097-108. doi: 10.1016/j.bmc.2012.08.032. Epub 2012 Aug 31. [22985961 ]
Target Details
4. Alpha-1B adrenergic receptor
General Function:
Protein heterodimerization activity
Specific Function:
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine (PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:
ADRA1B
Uniprot ID:
P35368
Molecular Weight:
56835.375 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.05012 uMNot AvailableBindingDB 50341448
References
  1. Procopiou PA, Browning C, Gore PM, Lynn SM, Richards SA, Slack RJ, Sollis SL: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists. Bioorg Med Chem. 2012 Oct 15;20(20):6097-108. doi: 10.1016/j.bmc.2012.08.032. Epub 2012 Aug 31. [22985961 ]
Target Details
5. Cytochrome P450 2D6
General Function:
Steroid hydroxylase 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 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC501 uMNot AvailableBindingDB 50341448
References
  1. Procopiou PA, Browning C, Buckley JM, Clark KL, Fechner L, Gore PM, Hancock AP, Hodgson ST, Holmes DS, Kranz M, Looker BE, Morriss KM, Parton DL, Russell LJ, Slack RJ, Sollis SL, Vile S, Watts CJ: The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis. J Med Chem. 2011 Apr 14;54(7):2183-95. doi: 10.1021/jm1013874. Epub 2011 Mar 7. [21381763 ]
Target Details
6. Histamine H3 receptor
General Function:
Histamine receptor activity
Specific Function:
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.
Gene Name:
HRH3
Uniprot ID:
Q9Y5N1
Molecular Weight:
48670.81 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.14791 uMNot AvailableBindingDB 50341448
References
  1. Procopiou PA, Browning C, Gore PM, Lynn SM, Richards SA, Slack RJ, Sollis SL: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists. Bioorg Med Chem. 2012 Oct 15;20(20):6097-108. doi: 10.1016/j.bmc.2012.08.032. Epub 2012 Aug 31. [22985961 ]
Target Details
7. Multidrug resistance protein 1
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5016 uMNot AvailableBindingDB 50341448
IC5030 uMNot AvailableBindingDB 50341448
References
  1. Katoh M, Nakajima M, Yamazaki H, Yokoi T: Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport. Eur J Pharm Sci. 2001 Feb;12(4):505-13. [11231118 ]