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Identification
Name Bosentan
Accession Number DB00559 (APRD00829)
Type small molecule
Groups approved
Description

Bosentan is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer®. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.
Structure Thumb
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Display: 2D Structure | 3D Structure
Synonyms
  • bosentan
  • Bosentan hydrate
Brand names
  • Tracleer (Actelion)
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
CAS number 147536-97-8
Weight Average: 551.614
Monoisotopic: 551.183854375
Chemical Formula C27H29N5O6S
InChI Key InChIKey=GJPICJJJRGTNOD-UHFFFAOYSA-N
InChI
InChI=1S/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32)
Plain Text
IUPAC Name
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
SMILES
COC1=C(OC2=C(OCCO)N=C(N=C2NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)C2=NC=CC=N2)C=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Cumenes and Derivatives
  • Benzenesulfonamides
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Sulfonyls
  • Ethers
  • Benzene and Derivatives
  • Cumenes and Derivatives
  • Benzenesulfonamides
  • Alcohols and Polyols
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Sulfonamides
  • Imines
  • Cyanamides
  • Phenyl Esters
Pharmacology
Indication Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).
Pharmacodynamics Bosentan 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. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.
Mechanism of action Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors.
Absorption Absolute bioavailability is approximately 50% and food does not affect absorption.
Volume of distribution
  • 18 L
Protein binding Greater than 98% to plasma proteins, mainly albumin.
Metabolism

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 4-(2-Hydroxy1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide methyl-hydroxylation
Cytochrome P450 3A4 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide O-demethylation
Cytochrome P450 2C9 4-(2-Hydroxy1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide methyl-hydroxylation
Cytochrome P450 2C9 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide O-demethylation
Route of elimination Bosentan is eliminated by biliary excretion following metabolism in the liver.
Half life Terminal elimination half-life is about 5 hours in healthy adult subjects.
Clearance
  • 4 L/h [patients with pulmonary arterial hypertension]
Toxicity Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Actelion ltd
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 125 mg
Tablet, film coated Oral 62.5 mg
Prices Not Available
Patents
Country Patent Number Approved Expires
United States 5292740 1995-11-20 2015-11-20
Canada 2071193 1998-08-25 2012-06-12
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5). PhysProp
logP 3.7 PhysProp
Caco2 permeability -5.98 [ADME Research, USCD] BiGG
Predicted Properties
Property Value Source
water solubility 9.04e-03 g/l ALOGPS
logP 4.18 ALOGPS
logP 4.94 ChemAxon Molconvert
logS -4.79 ALOGPS
pKa 15.10 ChemAxon Molconvert
hydrogen acceptor count 9 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 145.65 ChemAxon Molconvert
rotatable bond count 10 ChemAxon Molconvert
refractivity 166.66 ChemAxon Molconvert
polarizability 57.89 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01227 Link_out
PubChem Compound 104865 Link_out
PubChem Substance 46507154 Link_out
ChemSpider 94651 Link_out
ChEBI 51450 Link_out
ChEMBL 51450 Link_out
Therapeutic Targets Database DNC000341 Link_out
PharmGKB PA10034 Link_out
Drug Product Database 2244982 Link_out
RxList http://www.rxlist.com/cgi/generic3/tracleer.htm Link_out
Drugs.com http://www.drugs.com/cdi/bosentan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Bosentan Link_out
ATC Codes
  • C02KX01
AHFS Codes
  • 24:12.92
PDB Entries Not Available
FDA label show (423.9 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Endothelin-1 receptor

Pharmacological action: yes
Actions: antagonist

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

Organism class: human
UniProt ID: P25101 Link_out
Gene: EDNRA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. 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
  4. 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
  5. Martin C, Held HD, Uhlig S: Differential effects of the mixed ET/ET-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. Pubmed
  6. 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

2. Endothelin B receptor

Pharmacological action: yes
Actions: antagonist

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

Organism class: human
UniProt ID: P24530 Link_out
Gene: EDNRB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. 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
  3. 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
  4. Marano G, Palazzesi S, Bernucci P, Grigioni M, Formigari R, Ballerini L: ET/ET receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. Life Sci. 1998;63(18):PL259-66. Pubmed
  5. 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
  6. 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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inducer

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. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Dingemanse J, Schaarschmidt D, van Giersbergen PL: Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301. Pubmed
  2. Dingemanse J, van Giersbergen PL: Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. Pubmed
  3. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Actions: substrate, inducer

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

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Bile salt export pump

Actions: inhibitor

Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes

UniProt ID: O95342 Link_out
Gene: ABCB11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ: The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 Apr;69(4):223-31. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:04

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.