Details
Stereochemistry | ACHIRAL |
Molecular Formula | C27H29N5O6S.H2O |
Molecular Weight | 569.629 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
O.COC1=CC=CC=C1OC2=C(OCCO)N=C(N=C2NS(=O)(=O)C3=CC=C(C=C3)C(C)(C)C)C4=NC=CC=N4
InChI
InChIKey=SXTRWVVIEPWAKM-UHFFFAOYSA-N
InChI=1S/C27H29N5O6S.H2O/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);1H2
Molecular Formula | C27H29N5O6S |
Molecular Weight | 551.614 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
Molecular Formula | H2O |
Molecular Weight | 18.0153 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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. Bosentan competitively antagonizes the binding of 125I-labeled ET-1 to human vascular smooth muscle cells (predominantly
ETA receptors) with an inhibition constant (Ki )
of 4.7 nM and to human placenta membranes (predominantly
ETB receptors) with a Ki of 95 nM. Furthermore,
bosentan is specific for endothelin receptors and
does not interfere with the binding of a variety of peptides,
neurotransmitters, growth factors, or eicosanoids to their
receptors.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2096678 |
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Target ID: CHEMBL4566 |
4.7 nM [Ki] | ||
Target ID: CHEMBL1785 |
95.0 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | TRACLEER Approved UseTracleer is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) (1.1). Considerations for use: Consider whether benefits offset the risk of hepatotoxicity in WHO Class II patients. Early hepatotoxicity may preclude future use as disease progresses (1.1). 1.1 Pulmonary Arterial Hypertension Tracleer® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1) Launch Date2001 |
PubMed
Title | Date | PubMed |
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Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. | 2000 Aug |
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Pharmacological regulation of postischemic sinusoidal diameters in rats--a new approach for reducing hepatic ischemia/reperfusion injury. | 2001 |
|
Endothelin receptor antagonist activity of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy)acetamide hydrochloride (PABSA) in rat aortic smooth muscle cells and isolated rat thoracic aorta. | 2001 |
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Improvement of respiratory function by bosentan during endotoxic shock in the pig. | 2001 Aug |
|
Endothelin receptor blockade improves endothelial function in human internal mammary arteries. | 2001 Jan |
|
Long-term endothelin receptor blockade improves cardiovascular function in diabetes. | 2001 Jul |
|
Endothelin mediates some of the renal actions of acutely administered angiotensin II. | 2001 Jul |
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Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? | 2001 May |
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Combined angiotensin and endothelin receptor blockade attenuates adverse cardiac remodeling post-myocardial infarction in the rat: possible role of transforming growth factor beta(1). | 2001 May |
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Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. | 2001 Nov |
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Endogenous endothelins mediate increased acidification in remnant kidneys. | 2001 Sep |
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Growth factors in idiopathic pulmonary fibrosis: relative roles. | 2002 |
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In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. | 2002 Apr |
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Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes. | 2002 Apr |
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Bosentan (Tracleer) for pulmonary arterial hypertension. | 2002 Apr 1 |
|
Tracleer. Tablets ease symptoms of rare lung disorder. | 2002 Feb |
|
Direct left ventricular wall stretch activates GATA4 binding in perfused rat heart: involvement of autocrine/paracrine pathways. | 2002 Jan |
|
[The effects of endothelin blockade on renal expression of angiotensin II type 1 receptor in diabetic hypertensive rats]. | 2002 Jan 10 |
|
[Bosentan in pulmonary hypertension]. | 2002 Mar |
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Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure. | 2002 Mar |
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Bosentan enters market with risk management program. | 2002 Mar 15 |
|
Treatment of primary pulmonary hypertension -- the next generation. | 2002 Mar 21 |
|
Bosentan therapy for pulmonary arterial hypertension. | 2002 Mar 21 |
Sample Use Guides
Initiate at 62.5 mg twice daily with or without food for 4 weeks,
and then increase to 125 mg twice daily
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8637410
Curator's Comment: In vitro, bosentan inhibits the contractions of isolated rat trachea induced by
ET-1 in a concentration-dependent manner (1-100 uM). https://www.ncbi.nlm.nih.gov/pubmed/18729040
Competition studies show that, in the absence of human serum albumin, the IC50 value of Bosentan was 5.7 nM. Addition of increasing doses of human serum albumin incrementally decreased the potency of Bosentan to 122.7 nM.
Substance Class |
Chemical
Created
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admin
on
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on
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Record UNII |
Q326023R30
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Record Status |
Validated (UNII)
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NDF-RT |
N0000175581
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WHO-VATC |
QC02KX01
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FDA ORPHAN DRUG |
134200
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LIVERTOX |
NBK547999
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EMA ASSESSMENT REPORTS |
STAYVEER (AUTHORIZED SCLERODERMA, SYSTEMIC
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WHO-ATC |
C02KX01
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EMA ASSESSMENT REPORTS |
TRACLEER (AUTHORIZED: PLUMONARY HYPERTENSION, SYSTEMATIC SCLERODERMA)
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FDA ORPHAN DRUG |
267608
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FDA ORPHAN DRUG |
292209
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EU-Orphan Drug |
EU/3/03/139
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m2625
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157212-55-0
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Bosentan
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185462
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1076115
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BOSENTAN
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C086232
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CHEMBL957
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TRANSPORTER -> INHIBITOR | |||
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BINDER->LIGAND |
BINDING
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IMPURITY -> PARENT |
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IMPURITY -> PARENT | |||
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IMPURITY -> PARENT |
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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Volume of Distribution | PHARMACOKINETIC |
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