Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:27:18 UTC
Update Date2014-12-24 20:25:52 UTC
Accession NumberT3D2844
Identification
Common NameAstemizole
ClassSmall Molecule
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 It was withdrawn from market by the manufacturer in 1999 due to the potential to cause arrhythmias at high doses, especially when when taken with CYP inhibitors or grapefruit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.
Compound Type
  • Amine
  • Anti-Allergic Agent
  • Drug
  • Ether
  • Histamine Antagonist
  • Histamine H1 Antagonist, Non-Sedating
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1-(P-Fluorobenzyl)-2-((1-(2-(P-methoxyphenyl)ethyl)piperid-4-yl)amino)benzimidazole
1-(P-Fluorobenzyl)-2-((1-(P-methoxyphenethyl)-4-piperidyl)amino)benzimidazole
Acemiz
Alerkin
Astemison
Astemizol
Astémizole
Astemizolum
Astesen
Hismanal
Histalong
Lergibrumizol
Stemiz
Chemical FormulaC28H31FN4O
Average Molecular Mass458.570 g/mol
Monoisotopic Mass458.248 g/mol
CAS Registry Number68844-77-9
IUPAC Name1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-1,3-benzodiazol-2-amine
Traditional Nameastemizole
SMILESCOC1=CC=C(CCN2CCC(CC2)N=C2NC3=CC=CC=C3N2CC2=CC=C(F)C=C2)C=C1
InChI IdentifierInChI=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 KeyInChIKey=GXDALQBWZGODGZ-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds 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).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzimidazoles
Sub ClassNot Available
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
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point149.1°C
Boiling PointNot Available
Solubility432 mg/L
LogP5.8
Predicted Properties
PropertyValueSource
Water Solubility0.0012 g/LALOGPS
logP5.92ALOGPS
logP5.39ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)8.75ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.32 ŲChemAxon
Rotatable Bond Count8ChemAxon
Refractivity135.64 m³·mol⁻¹ChemAxon
Polarizability52.08 ųChemAxon
Number of Rings5ChemAxon
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, Positivesplash10-0a4i-1922000000-2742ecd8a8c6af4db428View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0110900000-7c47b2813568251daf1eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-052r-1947600000-b67040fd618da0f36a6aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0016-2940000000-e1a0cda3eae5d6bc1cf6View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0010900000-e80e4e306be153aeab7cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0abc-0145900000-d00ee25e0101b4beb25aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01qd-3893000000-dae89e0c7d17da3e1c78View in MoNA
Toxicity Profile
Route of ExposureOral. Rapidly absorbed from the gastrointestinal tract.
Mechanism of ToxicityAstemizole competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H3-receptors, producing adverse effects.
MetabolismIt is metabolized by CYP3A4. [Wikidpedia]. Almost completely metabolized in the liver and primarily excreted in the feces. Half Life: 1 day
Toxicity ValuesLD50: 2052mg/kg (Mouse) (3)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesAstemizole tablets are indicated for the relief of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. (5). Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias.
Minimum Risk LevelNot Available
Health EffectsCardiovascular adverse events. In some cases, recognition of severe arrhythmias has been preceded by episodes of syncope. Similarly, rare cases of hypotension, palpitations, and dizziness have also been reported with Astemizole use, which may reflect undetected ventricular arrhythmia. (5)
SymptomsNot Available
TreatmentIn the event of overdosage, supportive measures including gastric lavage and emesis should be employed. (6)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00637
HMDB IDHMDB14775
PubChem Compound ID2247
ChEMBL IDCHEMBL296419
ChemSpider ID2160
KEGG IDC06832
UniProt IDNot Available
OMIM ID
ChEBI ID2896
BioCyc IDNot Available
CTD IDNot Available
Stitch IDAstemizole
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkAstemizole
References
Synthesis Reference

Godelieve Irma Christine Maria Heylen, Cornelus Gerardus Maria Janssen, Jurzak Mirek, Henricus Petrus Martinus Maria Van Assouw, “Radiolabeled astemizole and method of making.” U.S. Patent US07541476, issued June 02, 2009.

MSDSLink
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. [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. [16816845 ]
  3. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  4. Drugs.com [Link]
  5. RxList fact sheet for Astemizole. [Link]
  6. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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
Inhibitory0.0029 uMNot AvailableBindingDB 24226
Inhibitory0.003 uMNot AvailableBindingDB 24226
Inhibitory0.0128 uMNot AvailableBindingDB 24226
IC500.0009 uMNot AvailableBindingDB 24226
IC500.00091 uMNot AvailableBindingDB 24226
IC500.000912 uMNot AvailableBindingDB 24226
IC500.0015 uMNot AvailableBindingDB 24226
IC500.006 uMNot AvailableBindingDB 24226
IC500.008 uMNot AvailableBindingDB 24226
IC500.01 uMNot AvailableBindingDB 24226
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. [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. [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. [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. [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. [15272206 ]
  6. 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 ]
  7. Pearlstein R, Vaz R, Rampe D: Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. J Med Chem. 2003 May 22;46(11):2017-22. [12747773 ]
  8. Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S: An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J Med Chem. 2006 Jun 1;49(11):3116-35. [16722631 ]
  9. 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 ]
  10. 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 ]
  11. Du LP, Tsai KC, Li MY, You QD, Xia L: The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents. Bioorg Med Chem Lett. 2004 Sep 20;14(18):4771-7. [15324906 ]
  12. Keseru GM: Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett. 2003 Aug 18;13(16):2773-5. [12873512 ]
  13. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
  14. Tobita M, Nishikawa T, Nagashima R: A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2886-90. [15911273 ]
  15. Jia L, Sun H: Support vector machines classification of hERG liabilities based on atom types. Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16. [18448342 ]
  16. Singleton DH, Boyd H, Steidl-Nichols JV, Deacon M, Groot MJ, Price D, Nettleton DO, Wallace NK, Troutman MD, Williams C, Boyd JG: Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel. J Med Chem. 2007 Jun 28;50(13):2931-41. Epub 2007 May 31. [17536794 ]
  17. Taglialatela M, Secondo A, Fresi A, Rosati B, Pannaccione A, Castaldo P, Giorgio G, Wanke E, Annunziato L: Inhibition of depolarization-induced [3H]noradrenaline release from SH-SY5Y human neuroblastoma cells by some second-generation H(1) receptor antagonists through blockade of store-operated Ca(2+) channels (SOCs). Biochem Pharmacol. 2001 Nov 1;62(9):1229-38. [11705456 ]
  18. Wang J, Della Penna K, Wang H, Karczewski J, Connolly TM, Koblan KS, Bennett PB, Salata JJ: Functional and pharmacological properties of canine ERG potassium channels. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H256-67. Epub 2002 Oct 3. [12388285 ]
  19. Taglialatela M, Pannaccione A, Castaldo P, Giorgio G, Zhou Z, January CT, Genovese A, Marone G, Annunziato L: Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines. Mol Pharmacol. 1998 Jul;54(1):113-21. [9658196 ]
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
Inhibitory0.0008 uMNot AvailableBindingDB 24226
Inhibitory0.00209 uMNot AvailableBindingDB 24226
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. 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 ]
  3. 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. [8001268 ]
  4. 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. [6146346 ]
  5. Kaliner MA, Check WA: Non-sedating antihistamines. Allergy Proc. 1988 Nov-Dec;9(6):649-63. [3147222 ]
  6. 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. [10597866 ]
  7. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [8935801 ]
  8. Wagner E, Wittmann HJ, Elz S, Strasser A: Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH(1)R, but low affinity to hH(4)R. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6274-80. doi: 10.1016/j.bmcl.2011.09.001. Epub 2011 Sep 8. [21944853 ]
General Function:
Vitamin d3 25-hydroxylase 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 (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. [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. [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. [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. [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. [15684493 ]
General Function:
Somatostatin receptor activity
Specific Function:
Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization.
Gene Name:
SSTR5
Uniprot ID:
P35346
Molecular Weight:
39201.925 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory4.07 uMNot AvailableBindingDB 24226
References
  1. Martin RE, Green LG, Guba W, Kratochwil N, Christ A: Discovery of the first nonpeptidic, small-molecule, highly selective somatostatin receptor subtype 5 antagonists: a chemogenomics approach. J Med Chem. 2007 Dec 13;50(25):6291-4. Epub 2007 Nov 19. [18020390 ]
  2. Martin RE, Mohr P, Maerki HP, Guba W, Kuratli C, Gavelle O, Binggeli A, Bendels S, Alvarez-Sanchez R, Alker A, Polonchuk L, Christ AD: Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6106-13. doi: 10.1016/j.bmcl.2009.09.024. Epub 2009 Sep 12. [19786348 ]
General Function:
Vitamin d3 25-hydroxylase 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 (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC503.3 uMNot AvailableBindingDB 24226
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. [12699389 ]
General Function:
Syndecan binding
Specific Function:
Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.
Gene Name:
HPSE
Uniprot ID:
Q9Y251
Molecular Weight:
61148.17 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation>1000 uMNot AvailableBindingDB 24226
References
  1. Gozalbes R, Mosulen S, Orti L, Rodriguez-Diaz J, Carbajo RJ, Melnyk P, Pineda-Lucena A: Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches. Bioorg Med Chem. 2013 Apr 1;21(7):1944-51. doi: 10.1016/j.bmc.2013.01.033. Epub 2013 Jan 31. [23415087 ]
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
Inhibitory7.94328 uMNot AvailableBindingDB 24226
References
  1. Wagner E, Wittmann HJ, Elz S, Strasser A: Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH(1)R, but low affinity to hH(4)R. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6274-80. doi: 10.1016/j.bmcl.2011.09.001. Epub 2011 Sep 8. [21944853 ]
General Function:
Structural constituent of cytoskeleton
Specific Function:
Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.
Gene Name:
MAPT
Uniprot ID:
P10636
Molecular Weight:
78927.025 Da
References
  1. Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB: Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease. J Alzheimers Dis. 2010;19(2):573-89. doi: 10.3233/JAD-2010-1262. [20110603 ]
General Function:
Monovalent cation:proton antiporter activity
Specific Function:
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:
SLC47A1
Uniprot ID:
Q96FL8
Molecular Weight:
61921.585 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5026.4 uMNot AvailableBindingDB 24226
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
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
IC500.3 uMNot AvailableBindingDB 24226
IC501.3 uMNot AvailableBindingDB 24226
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. [12699389 ]
General Function:
Phosphorelay sensor kinase activity
Specific Function:
Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel (PubMed:22732247). Channel properties may be modulated by subunit assembly, but not by cyclic nucleotides (By similarity). Mediates IK(NI) current in myoblasts (PubMed:9738473). Involved in the regulation of cell proliferation and differentiation, in particular adipogenic and osteogenic differentiation in bone marrow-derived mesenchymal stem cells (MSCs) (PubMed:23881642).
Gene Name:
KCNH1
Uniprot ID:
O95259
Molecular Weight:
111421.76 Da
References
  1. Roy J, Vantol B, Cowley EA, Blay J, Linsdell P: Pharmacological separation of hEAG and hERG K+ channel function in the human mammary carcinoma cell line MCF-7. Oncol Rep. 2008 Jun;19(6):1511-6. [18497958 ]
General Function:
Somatostatin receptor activity
Specific Function:
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.
Gene Name:
SSTR2
Uniprot ID:
P30874
Molecular Weight:
41332.37 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 24226
References
  1. Martin RE, Mohr P, Maerki HP, Guba W, Kuratli C, Gavelle O, Binggeli A, Bendels S, Alvarez-Sanchez R, Alker A, Polonchuk L, Christ AD: Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6106-13. doi: 10.1016/j.bmcl.2009.09.024. Epub 2009 Sep 12. [19786348 ]
General Function:
Somatostatin receptor activity
Specific Function:
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase.
Gene Name:
SSTR3
Uniprot ID:
P32745
Molecular Weight:
45846.995 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 24226
References
  1. Martin RE, Mohr P, Maerki HP, Guba W, Kuratli C, Gavelle O, Binggeli A, Bendels S, Alvarez-Sanchez R, Alker A, Polonchuk L, Christ AD: Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6106-13. doi: 10.1016/j.bmcl.2009.09.024. Epub 2009 Sep 12. [19786348 ]
General Function:
Somatostatin receptor activity
Specific Function:
Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells.
Gene Name:
SSTR4
Uniprot ID:
P31391
Molecular Weight:
42002.245 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 24226
References
  1. Martin RE, Mohr P, Maerki HP, Guba W, Kuratli C, Gavelle O, Binggeli A, Bendels S, Alvarez-Sanchez R, Alker A, Polonchuk L, Christ AD: Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6106-13. doi: 10.1016/j.bmcl.2009.09.024. Epub 2009 Sep 12. [19786348 ]
General Function:
Ubiquitin-protein transferase activity
Specific Function:
The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes.
Gene Name:
UBE2N
Uniprot ID:
P61088
Molecular Weight:
17137.625 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>20 uMNot AvailableBindingDB 24226
References
  1. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]