Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C27H29N5O6S |
| Molecular Weight | 551.6162 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)(C)c1ccc(cc1)S(=O)(=O)Nc2c(c(nc(-c3ncccn3)n2)OCCO)Oc4ccccc4OC
InChI
InChIKey=GJPICJJJRGTNOD-UHFFFAOYSA-N
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)
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 |
|---|---|---|---|
Target ID: CHEMBL2096678 |
|||
| 4.7 nM [Ki] | |||
| 95.0 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| 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 Date1.00621438E12 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Current management of primary pulmonary hypertension. | 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 |
|
| The loop diuretic torasemide interferes with endothelin-1 actions in the aorta of hypertensive rats. | 2001 |
|
| Improvement of respiratory function by bosentan during endotoxic shock in the pig. | 2001 Aug |
|
| The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure. | 2001 Aug |
|
| Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation. | 2001 Aug |
|
| Report From the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001. | 2001 Aug 28 |
|
| Small bowel review: diseases of the small intestine. | 2001 Dec |
|
| Pulmonary hypertension associated with COPD. | 2001 Dec |
|
| Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta. | 2001 Dec |
|
| Role of endogenous endothelin on coronary reflow after cardioplegic arrest. | 2001 Dec |
|
| Endothelin antagonist reduces hemodynamic responses to vasopressin in DOCA-salt hypertension. | 2001 Dec |
|
| Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat. | 2001 Dec |
|
| Endothelin and heart failure. | 2001 Dec |
|
| Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats. | 2001 Dec 7 |
|
| New pharmacological strategies for the treatment of heart failure. | 2001 Jul |
|
| 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 |
|
| Influence of nitric oxide synthase inhibition and endothelin-1 receptor blockade on acetylcholine-induced coronary artery contraction in vitro in dilated and ischemic cardiomyopathies. | 2001 Jul |
|
| Effects of the endothelin receptor antagonist Bosentan on ischaemia/reperfusion injury in rat skeletal muscle. | 2001 Jul 13 |
|
| Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure. | 2001 Jul 31 |
|
| Bosentan, an endothelin antagonist, augments hepatic graft function by reducing graft circulatory impairment following ischemia/reperfusion injury. | 2001 May-Jun |
|
| Rationale and perspective of endothelin-1 antagonism in acute heart failure. | 2001 Nov |
|
| Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. | 2001 Nov |
|
| Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1. | 2001 Nov |
|
| Endothelin-1 decreases glutamate uptake in primary cultured rat astrocytes. | 2001 Nov |
|
| Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane. | 2001 Nov-Dec |
|
| Endothelin receptor blockade and nitric oxide bioactivity. | 2001 Oct |
|
| Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor-no pathway. | 2001 Oct |
|
| Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives. | 2001 Oct 11 |
|
| Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. | 2001 Oct 6 |
|
| Endothelin involvement in respiratory centre activity. | 2001 Sep |
|
| Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats. | 2001 Sep |
|
| Endogenous endothelins mediate increased acidification in remnant kidneys. | 2001 Sep |
|
| In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. | 2002 Apr |
|
| Bosentan (Tracleer) for pulmonary arterial hypertension. | 2002 Apr 1 |
|
| Tracleer. Tablets ease symptoms of rare lung disorder. | 2002 Feb |
|
| Endothelin antagonists and heart failure. | 2002 Feb |
|
| Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. | 2002 Feb 20 |
|
| Human endothelin subtype A receptor enhancement during tissue culture via de novo transcription. | 2002 Jan |
|
| Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure. | 2002 Jan |
|
| Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins. | 2002 Jan |
|
| [Physical endurance improves markedly. New therapy approach in pulmonary hypertension]. | 2002 Jan 17 |
|
| Tracleer (bosentan). | 2002 Jan-Feb |
|
| [Bosentan in pulmonary hypertension]. | 2002 Mar |
|
| Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure. | 2002 Mar |
|
| Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. | 2002 Mar |
|
| 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
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.
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NDF-RT |
N0000175581
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N0000175364
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WHO-ATC |
C02KX01
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C81107
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147536-97-8
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M2625
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147536-97-8
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DB00559
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1468845
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104865
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7195
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)
