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Approved, Investigational, Withdrawn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

Pharmacology

Indication

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

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Contraindications & Blackbox Warnings
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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.

Target Actions Organism
AEndothelin-1 receptor
antagonist
 Humans
UEndothelin B receptor
antagonist
 Humans
吸收

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%)

半life

10个小时

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

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

Interactions

Drug InteractionsLearn More" title="" 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.
Drug Interaction
整合药物之间
interactions in your software
Abatacept The metabolism of Sitaxentan can be increased when combined with Abatacept.
Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Sitaxentan.
Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Sitaxentan.
Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Sitaxentan.
Acebutolol Acebutolol may increase the hypotensive activities of Sitaxentan.
Aceclofenac The therapeutic efficacy of Sitaxentan can be decreased when used in combination with Aceclofenac.
Acemetacin The therapeutic efficacy of Sitaxentan can be decreased when used in combination with Acemetacin.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Sitaxentan.
Acetohexamide 的新陈代谢Acetohexamide可以降低when combined with Sitaxentan.
Acetyl sulfisoxazole The metabolism of Sitaxentan can be decreased when combined with Acetyl sulfisoxazole.
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Food Interactions
  • Take with or without food.

Products

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Product Ingredients
Ingredient UNII CAS InChI Key
Sitaxentan sodium 6V9JH46E20 210421-74-2 MDTNUYUCUYPIHE-UHFFFAOYSA-N
Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Thelin Tablet, film coated 100 mg Oral Pfizer 2016-09-08 2011-03-03 EU flag
Thelin Tablet, film coated 100 mg Oral Pfizer 2016-09-08 2011-03-03 EU flag
Thelin Tablet, film coated 100 mg Oral Pfizer 2016-09-08 2011-03-03 EU flag
Thelin Tablet, film coated 100 mg Oral Pfizer 2016-09-08 2011-03-03 EU flag
Thelin Tablet, film coated 100 mg Oral Pfizer 2016-09-08 2011-03-03 EU flag
Thelin Tablet 100 mg Oral Pfizer Canada Ulc 2007-06-19 2011-04-30 Canada flag

Categories

ATC Codes
C02KX03 — Sitaxentan
Drug Categories
Chemical TaxonomyProvided byClassyfire
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 TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
3 Completed Treatment Pulmonary Hypertension (PH) 1
3 Terminated Not Available Pulmonary Arterial Hypertension (PAH) 1
3 Terminated Treatment Pulmonary Arterial Hypertension (PAH)/Pulmonary Hypertension (PH) 3
3 Terminated Treatment Pulmonary Hypertension (PH) 2
2 Completed Treatment Cardiac Surgery Subjects/Subjects Undergoing CABG and/or Cardiac Valve Replacement 1
2 Completed Treatment Chronic Kidney Disease (CKD)/CRD 1
2 Completed Treatment Heart Failure, Diastolic 1
2 Terminated Treatment Effect of Sitaxsentan on Airway Remodeling in Severe Asthma 1
2 Unknown Status Treatment Blood Pressures/Chronic Kidney Disease (CKD)/Proteinuria 1
2, 3 Unknown Status Treatment Pulmonary Hypertension (PH) 1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Form Route Strength
Tablet Oral 100 mg
Tablet, film coated Oral
Tablet, film coated Oral 100 mg
Prices
Not Available
Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region
CA2281090 No 2005-06-07 2018-04-02 Canada flag
CA2161346 No 2004-11-23 2014-05-20 Canada flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
Property Value Source
Water Solubility 0.0181 mg/mL ALOGPS
logP 3.35 ALOGPS
logP 3.09 Chemaxon
logS -4.4 ALOGPS
pKa (Strongest Acidic) 6.89 Chemaxon
pKa (Strongest Basic) 0.75 Chemaxon
Physiological Charge -1 Chemaxon
Hydrogen Acceptor Count 6 Chemaxon
Hydrogen Donor Count 1 Chemaxon
Polar Surface Area 107.73 Å2 Chemaxon
Rotatable Bond Count 5 Chemaxon
Refractivity 105.8 m3·mol-1 Chemaxon
Polarizability 43.12 Å3 Chemaxon
Number of Rings 4 Chemaxon
Bioavailability 1 Chemaxon
Rule of Five Yes Chemaxon
Ghose Filter Yes Chemaxon
Veber's Rule No Chemaxon
MDDR-like Rule No Chemaxon
Predicted ADMET Features
Property Value Probability
Human Intestinal Absorption + 0.9811
Blood Brain Barrier + 0.511
Caco-2 permeable - 0.5662
P-glycoprotein substrate Non-substrate 0.8285
P-glycoprotein inhibitor I Non-inhibitor 0.8519
P-glycoprotein inhibitor II Non-inhibitor 0.8682
Renal organic cation transporter Non-inhibitor 0.9158
CYP450 2C9 substrate Non-substrate 0.8057
CYP450 2D6 substrate Non-substrate 0.8266
CYP450 3A4 substrate Non-substrate 0.5263
CYP450 1A2 substrate Non-inhibitor 0.6693
CYP450 2C9 inhibitor Inhibitor 0.7225
CYP450 2D6 inhibitor Non-inhibitor 0.8052
CYP450 2C19 inhibitor Non-inhibitor 0.5
CYP450 3A4 inhibitor Inhibitor 0.925
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9157
Ames test Non AMES toxic 0.634
Carcinogenicity Non-carcinogens 0.5575
Biodegradation Not ready biodegradable 0.9958
Rat acute toxicity 2.5528 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9901
hERG inhibition (predictor II) Non-inhibitor 0.9051
ADMET data is predicted usingadmetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Spectrum Spectrum Type Splash Key
Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available

Targets

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insights and accelerate drug research.
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Details 1.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
分子量
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]
Details 2.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
分子量
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

Details 1.Cytochrome P450 2C19
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
负责一些其他的新陈代谢apeutic 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
分子量
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]
Details 2.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
分子量
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]
Details 3.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
分子量
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 January 02, 2022 12:00