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Record Information
Version5.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:52 UTC
Update Date2022-03-07 02:52:03 UTC
HMDB IDHMDB0015629
Secondary Accession Numbers
  • HMDB15629
Metabolite Identification
Common NameSitaxentan
DescriptionSitaxentan, also known as TBC-11251, belongs to the class of organic compounds known as benzodioxoles. These are organic compounds containing a benzene ring fused to either isomers of dioxole. Dioxole is a five-membered unsaturated ring of two oxygen atoms and three carbon atoms. Sitaxentan is an extremely weak basic (essentially neutral) compound (based on its pKa). Sitaxentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. Sitaxentan is only found in individuals that have used or taken this drug. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, Sitaxentan decreases pulmonary vascular resistance. Sitaxentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Sitaxentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs).
Structure
Data?1582753318
Synonyms
ValueSource
SitaxsentanHMDB
TBC-11251HMDB
N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methyl)phenylacetyl-3-thiophenesulfonamideMeSH
N-(4-Chloro-3-methyl-5-isoxazolyl)-2-((4,5-(methylenedioxy)-O-toly)acetyl)-3-thiophenesulfonamideMeSH
Chemical FormulaC18H15ClN2O6S2
Average Molecular Weight454.905
Monoisotopic Molecular Weight454.006005309
IUPAC NameN-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide
Traditional Namethelin
CAS Registry Number210421-64-0
SMILES
CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC2=CC3=C(OCO3)C=C2C)=C1Cl
InChI Identifier
InChI=1S/C18H15ClN2O6S2/c1-9-5-13-14(26-8-25-13)7-11(9)6-12(22)17-15(3-4-28-17)29(23,24)21-18-16(19)10(2)20-27-18/h3-5,7,21H,6,8H2,1-2H3
InChI KeyPHWXUGHIIBDVKD-UHFFFAOYSA-N
Chemical Taxonomy
Description Belongs to the class of organic compounds known as benzodioxoles. These are organic compounds containing a benzene ring fused to either isomers of dioxole. Dioxole is a five-membered unsaturated ring of two oxygen atoms and three carbon atoms.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzodioxoles
Sub ClassNot Available
Direct ParentBenzodioxoles
Alternative Parents
Substituents
  • Benzodioxole
  • Aryl alkyl ketone
  • Aryl ketone
  • Aryl chloride
  • Aryl halide
  • Benzenoid
  • Organosulfonic acid amide
  • Azole
  • Isoxazole
  • Heteroaromatic compound
  • Organic sulfonic acid or derivatives
  • Organosulfonic acid or derivatives
  • Aminosulfonyl compound
  • Thiophene
  • Sulfonyl
  • Ketone
  • Oxacycle
  • Acetal
  • Azacycle
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Ontology
Physiological effectNot Available
Disposition
ProcessNot Available
RoleNot Available
Physical Properties
StateSolid
Experimental Molecular Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Experimental Chromatographic PropertiesNot Available
Predicted Molecular Properties
PropertyValueSource
Water Solubility0.018 g/LALOGPS
logP3.35ALOGPS
logP3.09ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)6.89ChemAxon
pKa (Strongest Basic)0.75ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area107.73 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity105.8 m³·mol⁻¹ChemAxon
Polarizability43.12 ųChemAxon
Number of Rings4ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted Chromatographic Properties

Predicted Collision Cross Sections

PredictorAdduct TypeCCS Value (Å2)Reference
DeepCCS[M+H]+190.09130932474
DeepCCS[M-H]-187.70930932474
DeepCCS[M-2H]-221.89630932474
DeepCCS[M+Na]+196.94630932474
AllCCS[M+H]+199.432859911
AllCCS[M+H-H2O]+196.932859911
AllCCS[M+NH4]+201.732859911
AllCCS[M+Na]+202.332859911
AllCCS[M-H]-194.532859911
AllCCS[M+Na-2H]-194.432859911
AllCCS[M+HCOO]-194.532859911

Predicted Kovats Retention Indices

Underivatized

MetaboliteSMILESKovats RI ValueColumn TypeReference
SitaxentanCC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC2=CC3=C(OCO3)C=C2C)=C1Cl5295.1Standard polar33892256
SitaxentanCC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC2=CC3=C(OCO3)C=C2C)=C1Cl3457.5Standard non polar33892256
SitaxentanCC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC2=CC3=C(OCO3)C=C2C)=C1Cl3474.4Semi standard non polar33892256

Derivatized

Derivative Name / StructureSMILESKovats RI ValueColumn TypeReference
Sitaxentan,1TMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C)C=CS1)OCO23456.3Semi standard non polar33892256
Sitaxentan,1TMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C)C=CS1)OCO23365.5Standard non polar33892256
Sitaxentan,1TMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C)C=CS1)OCO25007.4Standard polar33892256
Sitaxentan,1TBDMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C(C)(C)C)C=CS1)OCO23656.7Semi standard non polar33892256
Sitaxentan,1TBDMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C(C)(C)C)C=CS1)OCO23580.1Standard non polar33892256
Sitaxentan,1TBDMS,isomer #1CC1=CC2=C(C=C1CC(=O)C1=C(S(=O)(=O)N(C3=C(Cl)C(C)=NO3)[Si](C)(C)C(C)(C)C)C=CS1)OCO24988.4Standard polar33892256
Spectra

GC-MS Spectra

Spectrum TypeDescriptionSplash KeyDeposition DateSourceView
Predicted GC-MSPredicted GC-MS Spectrum - Sitaxentan GC-MS (Non-derivatized) - 70eV, Positivesplash10-0002-2911100000-bc2a1c237a5d20fc7fdd2017-09-01Wishart LabView Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - Sitaxentan GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12Wishart LabView Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - Sitaxentan GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12Wishart LabView Spectrum

MS/MS Spectra

Spectrum TypeDescriptionSplash KeyDeposition DateSourceView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 10V, Positive-QTOFsplash10-0a4i-0012900000-ce9abb5f9d34eeec4e752016-08-01Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 20V, Positive-QTOFsplash10-0a4r-0953700000-bf4f0740a903bbe272bb2016-08-01Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 40V, Positive-QTOFsplash10-052u-3390000000-26c07fb81659836de3aa2016-08-01Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 10V, Negative-QTOFsplash10-0udi-0001900000-89731203423f9c2c4f612016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 20V, Negative-QTOFsplash10-004i-1291600000-b346cc1802382a37696a2016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 40V, Negative-QTOFsplash10-0a4l-9410000000-8a91a08da2a0b22f85af2016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 10V, Positive-QTOFsplash10-0a4i-0001900000-4603fc4b43ea34c94da32021-10-11Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 20V, Positive-QTOFsplash10-0006-0900200000-4603223331cb368e057e2021-10-11Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 40V, Positive-QTOFsplash10-009t-1930100000-1655132c3e1392943c272021-10-11Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 10V, Negative-QTOFsplash10-0udi-0000900000-c85f93916432b4dbe2892021-10-11Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 20V, Negative-QTOFsplash10-0udj-0136900000-dd6a50653785ff673c2c2021-10-11Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Sitaxentan 40V, Negative-QTOFsplash10-03di-2289500000-62d0e1afc39abb8eb9e82021-10-11Wishart LabView Spectrum
Biological Properties
Cellular Locations
  • Membrane
Biospecimen Locations
  • Blood
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB06268 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB06268 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB06268
Phenol Explorer Compound IDNot Available
FooDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID187436
KEGG Compound IDNot Available
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkSitaxentan
METLIN IDNot Available
PubChem Compound216235
PDB IDNot Available
ChEBI ID123417
Food Biomarker OntologyNot Available
VMH IDNot Available
MarkerDB IDNot Available
Good Scents IDNot Available
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General ReferencesNot 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. Stavros F, Kramer WG, Wilkins MR: The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects. Br J Clin Pharmacol. 2010 Jan;69(1):23-6. doi: 10.1111/j.1365-2125.2009.03541.x. [PubMed:20078609 ]
  2. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J: Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest. 2002 Jun;121(6):1860-8. [PubMed:12065350 ]
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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular weight:
55627.365
References
  1. Pulido T, Sandoval J, Roquet I, Gutierrez R, Rueda T, Pena H, Santos E, Miranda MT, Lupi E: Interaction of acenocoumarol and sitaxentan in pulmonary arterial hypertension. Eur J Clin Invest. 2009 Jun;39 Suppl 2:14-8. doi: 10.1111/j.1365-2362.2009.02116.x. [PubMed:19335742 ]
  2. Opitz CF, Ewert R, Kirch W, Pittrow D: Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008 Aug;29(16):1936-48. doi: 10.1093/eurheartj/ehn234. Epub 2008 Jun 17. [PubMed:18562303 ]
  3. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J: Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest. 2002 Jun;121(6):1860-8. [PubMed:12065350 ]
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. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J: Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest. 2002 Jun;121(6):1860-8. [PubMed:12065350 ]
General function:
Involved in G-protein coupled receptor protein signaling pathway
Specific function:
Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. The rank order of binding affinities for ET-A is:ET1 > ET2 >> ET3
Gene Name:
EDNRA
Uniprot ID:
P25101
Molecular weight:
48721.8
References
  1. Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, McLaughlin VV, Oudiz RJ, Robbins IM, Seibold JR, Shapiro S, Tapson VF, Barst RJ: Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis. 2007 Nov;66(11):1467-72. Epub 2007 May 1. [PubMed:17472992 ]
  2. Albertini M, Lafortuna CL, Ciminaghi B, Mazzola S, Clement MG: Endothelin involvement in respiratory centre activity. Prostaglandins Leukot Essent Fatty Acids. 2001 Sep;65(3):157-63. [PubMed:11728166 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  4. Kiowski W, Sutsch G, Oechslin E, Bertel O: Hemodynamic effects of bosentan in patients with chronic heart failure. Heart Fail Rev. 2001 Dec;6(4):325-34. [PubMed:11447307 ]
  5. Kramp R, Fourmanoir P, Caron N: Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat. Am J Physiol Renal Physiol. 2001 Dec;281(6):F1132-40. [PubMed:11704565 ]
  6. Martin C, Held HD, Uhlig S: Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. [PubMed:10961375 ]
  7. Sihvola RK, Pulkkinen VP, Koskinen PK, Lemstrom KB: Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. J Am Coll Cardiol. 2002 Feb 20;39(4):710-7. [PubMed:11849873 ]
General function:
Involved in G-protein coupled receptor protein signaling pathway
Specific function:
Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
Gene Name:
EDNRB
Uniprot ID:
P24530
Molecular weight:
49643.3
References
  1. Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, McLaughlin VV, Oudiz RJ, Robbins IM, Seibold JR, Shapiro S, Tapson VF, Barst RJ: Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis. 2007 Nov;66(11):1467-72. Epub 2007 May 1. [PubMed:17472992 ]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  3. Gardiner SM, Kemp PA, March JE, Bennett T: Effects of bosentan (Ro 47-0203), an ETA-, ETB-receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats. Br J Pharmacol. 1994 Jul;112(3):823-30. [PubMed:7921608 ]
  4. Gupta SK, Saxena A, Singh U, Arya DS: Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2005 Jul;275(1-2):67-74. [PubMed:16335785 ]
  5. Marano G, Palazzesi S, Bernucci P, Grigioni M, Formigari R, Ballerini L: ET(A)/ET(B) receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. Life Sci. 1998;63(18):PL259-66. [PubMed:9806221 ]
  6. Richard V, Kaeffer N, Hogie M, Tron C, Blanc T, Thuillez C: Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. Br J Pharmacol. 1994 Nov;113(3):869-76. [PubMed:7858879 ]
  7. Said SA, Ammar el SM, Suddek GM: Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res. 2005 Feb;51(2):107-15. [PubMed:15629255 ]