Identification

Name
Sitaxentan
Accession Number
DB06268
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Sitaxentan is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.

Structure
Thumb
Synonyms
  • Sitaxsentan
External IDs
IPI-1040 / TBC-11251
Product Ingredients
IngredientUNIICASInChI Key
Sitaxentan sodium6V9JH46E20210421-74-2MDTNUYUCUYPIHE-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ThelinTablet100 mgOralPfizer2007-06-192011-04-30Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
ThelinSitaxentan sodium (100 mg)Tablet, film coatedOralPfizer2006-08-102011-03-02Eu
ThelinSitaxentan sodium (100 mg)Tablet, film coatedOralPfizer2006-08-102011-03-02Eu
ThelinSitaxentan sodium (100 mg)Tablet, film coatedOralPfizer2006-08-102011-03-02Eu
ThelinSitaxentan sodium (100 mg)Tablet, film coatedOralPfizer2006-08-102011-03-02Eu
ThelinSitaxentan sodium (100 mg)Tablet, film coatedOralPfizer2006-08-102011-03-02Eu
Categories
UNII
J9QH779MEM
CAS number
184036-34-8
Weight
Average: 454.905
Monoisotopic: 454.006005309
Chemical Formula
C18H15ClN2O6S2
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

Pharmacology

Indication

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

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
Human
UEndothelin B receptor
antagonist
Human
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
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Sitaxentan.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Sitaxentan.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Sitaxentan.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Sitaxentan.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Sitaxentan.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Sitaxentan.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Sitaxentan.
AbirateroneThe metabolism of Sitaxentan can be decreased when combined with Abiraterone.
AcebutololAcebutolol may increase the hypotensive activities of Sitaxentan.
AceclofenacThe therapeutic efficacy of Sitaxentan can be decreased when used in combination with Aceclofenac.
Food Interactions
  • Take without regard to meals

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015629
KEGG Drug
D07171
PubChem Compound
216235
PubChem Substance
99443241
ChemSpider
187436
BindingDB
50058126
ChEBI
135736
ChEMBL
CHEMBL282724
PharmGKB
PA165958361
IUPHAR
3950
Guide to Pharmacology
GtP Drug Page
Wikipedia
Sitaxentan
ATC Codes
C02KX03 — Sitaxentan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic SciencePulmonary Arterial Hypertension (PAH) / Vasoconstriction / Vasodilation1
1CompletedTreatmentHealthy Volunteers1
1TerminatedTreatmentPulmonary Arterial Hypertension (PAH)1
1WithdrawnBasic SciencePulmonary Arterial Hypertension (PAH)2
2CompletedTreatmentChronic Kidney Disease (CKD) / CRD1
2CompletedTreatmentCardiac Surgery Subjects / Subjects Undergoing CABG and/or Cardiac Valve Replacement1
2CompletedTreatmentDiastolic Heart Failure1
2TerminatedTreatmentEffect of Sitaxsentan on Airway Remodeling in Severe Asthma1
2Unknown StatusTreatmentBlood Pressures / Chronic Kidney Disease (CKD) / Proteinuria1
2, 3Unknown StatusTreatmentPulmonary Hypertension (PH)1
3CompletedTreatmentPulmonary Hypertension (PH)1
3TerminatedNot AvailablePulmonary Arterial Hypertension (PAH)1
3TerminatedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)3
3TerminatedTreatmentPulmonary Hypertension (PH)2
Not AvailableCompletedNot AvailablePulmonary Arterial Hypertension (PAH)1
Not AvailableCompletedOtherHeart Diseases1
Not AvailableTerminatedNot AvailablePulmonary Arterial Hypertension (PAH)1
Not AvailableUnknown StatusNot AvailablePAH WHO Group I / Pulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)1

Pharmacoeconomics

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

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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Benzodioxole / Aryl alkyl ketone / Aryl ketone / Aryl chloride / Aryl halide / Benzenoid / Organosulfonic acid amide / Azole / Isoxazole / Heteroaromatic compound
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Endothelin-1 receptor
Kind
Protein
Organism
Human
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. [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]
Details
2. Endothelin B receptor
Kind
Protein
Organism
Human
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. [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]

Enzymes

Kind
Protein
Organism
Human
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. [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]
  4. Sitaxentan Monograph [File]
  5. NPS Medicinewise Australian Prescriber: New Drugs [File]
Kind
Protein
Organism
Human
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. [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]
Kind
Protein
Organism
Human
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. [PubMed:12065350]
  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. [PubMed:20406243]
  3. EMA Discussion Document, Sitaxentan [File]

Drug created on March 19, 2008 10:20 / Updated on November 02, 2018 08:46