NAV

Sitaxentan

Identification

Generic Name
Sitaxentan
DrugBank Accession Number
DB06268
Background

Sitaxentan was marketed under the trade name Thelin for the treatment of pulmonary arterial hypertension (PAH) by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market over concerns of hepatotoxicity.

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
3D
Similar Structures
Weight
Average: 454.905
Monoisotopic: 454.006005309
Chemical Formula
C18H15ClN2O6S2
Synonyms
  • Sitaxentan
  • Sitaxsentan
External IDs
  • IPI-1040
  • TBC-11251
Poor quality drug data slowing you down?
Unlock 38% more drug discovery time and eliminate decision-making doubts with this one-stop guide to quality drug data.
Download eBook
Poor quality drug data slowing you down?
Download eBook

Pharmacology

Indication

Investigated for use/treatment in pulmonary hypertension, connective tissue diseases, hypertension, and congestive heart failure.

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

Sitaxentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Sitaxentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Mechanism of action

Sitaxentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. 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 has a higher affinity for ET-A than ET-B.

TargetActionsOrganism
AEndothelin-1 receptor
antagonist
Humans
UEndothelin B receptor
antagonist
Humans
Absorption

70-100%

Volume of distribution

Not Available

Protein binding

99% +

Metabolism

Hepatic (CYP2C9- and CYP3A4-mediated)

Route of elimination

Renal (50 to 60%) Fecal (40 to 50%)

Half-life

10 hours

Clearance

Not Available

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
AbaloparatideAbaloparatide may increase the hypotensive activities of Sitaxentan.
AbataceptThe metabolism of Sitaxentan can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sitaxentan.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Sitaxentan.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Sitaxentan.
Food Interactions
  • Take with or without food.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Sitaxentan sodium6V9JH46E20210421-74-2MDTNUYUCUYPIHE-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ThelinTablet, film coated100 mgOralPfizer2016-09-082011-03-03EU flag
ThelinTablet, film coated100 mgOralPfizer2016-09-082011-03-03EU flag
ThelinTablet, film coated100 mgOralPfizer2016-09-082011-03-03EU flag
ThelinTablet100 mgOralPfizer Canada Ulc2007-06-192011-04-30Canada flag
ThelinTablet, film coated100 mgOralPfizer2016-09-082011-03-03EU flag

Categories

ATC Codes
C02KX03 — Sitaxentan
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodioxoles
Sub Class
Not Available
Direct Parent
Benzodioxoles
Alternative Parents
Aryl alkyl ketones / Organosulfonamides / Aryl chlorides / Benzenoids / Thiophenes / Aminosulfonyl compounds / Heteroaromatic compounds / Isoxazoles / Acetals / Oxacyclic compounds
show 6 more
Substituents
Acetal / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Aryl alkyl ketone / Aryl chloride / Aryl halide / Aryl ketone / Azacycle / Azole / Benzenoid
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
J9QH779MEM
CAS number
184036-34-8
InChI Key
PHWXUGHIIBDVKD-UHFFFAOYSA-N
InChI
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
IUPAC Name
N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide
SMILES
CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC2=CC3=C(OCO3)C=C2C)=C1Cl

References

General References
Not Available
Human Metabolome Database
HMDB0015629
KEGG Drug
D07171
PubChem Compound
216235
PubChem Substance
99443241
ChemSpider
187436
BindingDB
50058126
ChEBI
135736
ChEMBL
CHEMBL282724
ZINC
ZINC000001481831
PharmGKB
PA165958361
Guide to Pharmacology
GtP Drug Page
Wikipedia
Sitaxentan

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentPulmonary Hypertension (PH)1
3TerminatedNot AvailablePulmonary Arterial Hypertension (PAH)1
3TerminatedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)3
3TerminatedTreatmentPulmonary Hypertension (PH)2
2CompletedTreatmentCardiac Surgery Subjects / Subjects Undergoing CABG and/or Cardiac Valve Replacement1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral100 mg
Tablet, film coatedOral
Tablet, film coatedOral100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2281090No2005-06-072018-04-02Canada flag
CA2161346No2004-11-232014-05-20Canada flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0181 mg/mLALOGPS
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 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity105.8 m3·mol-1Chemaxon
Polarizability43.12 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9811
Blood Brain Barrier+0.511
Caco-2 permeable-0.5662
P-glycoprotein substrateNon-substrate0.8285
P-glycoprotein inhibitor INon-inhibitor0.8519
P-glycoprotein inhibitor IINon-inhibitor0.8682
Renal organic cation transporterNon-inhibitor0.9158
CYP450 2C9 substrateNon-substrate0.8057
CYP450 2D6 substrateNon-substrate0.8266
CYP450 3A4 substrateNon-substrate0.5263
CYP450 1A2 substrateNon-inhibitor0.6693
CYP450 2C9 inhibitorInhibitor0.7225
CYP450 2D6 inhibitorNon-inhibitor0.8052
CYP450 2C19 inhibitorNon-inhibitor0.5
CYP450 3A4 inhibitorInhibitor0.925
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9157
Ames testNon AMES toxic0.634
CarcinogenicityNon-carcinogens0.5575
BiodegradationNot ready biodegradable0.9958
Rat acute toxicity2.5528 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9901
hERG inhibition (predictor II)Non-inhibitor0.9051
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0002-2911100000-bc2a1c237a5d20fc7fdd
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ab9-0029700000-51bbc68f61bbbea400f5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0000900000-e568e04bc32192b4df83
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0244900000-f4672726e2dc613204d0
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f89-5331900000-37e11c0c97664ad6670e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052b-0961300000-3097bd383b0e7d509ec0
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-1390000000-a78f6b81aa9db3e266e6
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-204.2786539
predicted
DarkChem Lite v0.1.0
[M-H]-187.70885
predicted
DeepCCS 1.0 (2019)
[M+H]+204.9176539
predicted
DarkChem Lite v0.1.0
[M+H]+190.0908
predicted
DeepCCS 1.0 (2019)
[M+Na]+204.0749539
predicted
DarkChem Lite v0.1.0
[M+Na]+196.94594
predicted
DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Details1. Endothelin-1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
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:...
Gene Name
EDNRA
Uniprot ID
P25101
Uniprot Name
Endothelin-1 receptor
Molecular Weight
48721.76 Da
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. [Article]
  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. [Article]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
Details2. Endothelin B receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Peptide hormone binding
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
Uniprot Name
Endothelin B receptor
Molecular Weight
49643.255 Da
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. [Article]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]

Enzymes

Details1. Cytochrome P450 2C19
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase 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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
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. [Article]
  2. Raja SG: Endothelin receptor antagonists for pulmonary arterial hypertension: an overview. Cardiovasc Ther. 2010 Oct;28(5):e65-71. doi: 10.1111/j.1755-5922.2010.00158.x. [Article]
  3. EMA Discussion Document, Sitaxentan [File]
Details2. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
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. [Article]
  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. [Article]
  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. [Article]
  4. Sitaxentan Monograph [File]
  5. NPS Medicinewise Australian Prescriber: New Drugs [File]
Details3. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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. [Article]
  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. [Article]

Drug created at March 19, 2008 16:20 / Updated at December 02, 2023 07:01