Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C27H29N5O6S |
| Molecular Weight | 551.614 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=C(OC2=C(NS(=O)(=O)C3=CC=C(C=C3)C(C)(C)C)N=C(N=C2OCCO)C4=NC=CC=N4)C=CC=C1
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)
| 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 |
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 |
|---|---|---|
| Endothelin antagonism with bosentan: a review of potential applications. | 1999 Apr |
|
| Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. | 2000 Aug |
|
| 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 |
|
| Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1. | 2001 Apr |
|
| Role of endothelin and vasopressin in DOCA-salt hypertension. | 2001 Apr |
|
| Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat. | 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 antagonism in experimental ischemic heart failure: hemodynamic, structural and neurohumoral effects. | 2001 Dec |
|
| Therapeutic role of bosentan in hypertension: lessons from the model of perinephritic hypertension. | 2001 Dec |
|
| Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts. | 2001 Jan |
|
| Important role for endothelins in acute hepatic ischemia/reperfusion injury. | 2001 Jan-Feb |
|
| New pharmacological strategies for the treatment of heart failure. | 2001 Jul |
|
| Long-term endothelin receptor blockade improves cardiovascular function in diabetes. | 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 |
|
| Endothelium-dependent relaxation in response to low concentrations of bradykinin is enhanced by phosphoramidon, bosentan and BQ-123 in bovine coronary arteries in vitro. | 2001 Jun |
|
| Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 caused by serogroup A streptococci and prolongs survival in rat peritoneal sepsis. | 2001 Jun |
|
| Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective. | 2001 Mar |
|
| The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock. | 2001 Mar 2 |
|
| Update in pharmacologic treatment of hypertension. | 2001 May |
|
| Neurogenic inflammation in the context of migraine. | 2001 May 1 |
|
| Acute endothelin a receptor blockade in heart failure. | 2001 May 8 |
|
| Bosentan, an endothelin antagonist, augments hepatic graft function by reducing graft circulatory impairment following ischemia/reperfusion injury. | 2001 May-Jun |
|
| Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. | 2001 Nov |
|
| Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001. | 2001 Oct 9 |
|
| Growth factors in idiopathic pulmonary fibrosis: relative roles. | 2002 |
|
| Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes. | 2002 Apr |
|
| Tracleer. Tablets ease symptoms of rare lung disorder. | 2002 Feb |
|
| Medical management of primary pulmonary hypertension. | 2002 Feb |
|
| Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. | 2002 Feb 20 |
|
| Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure. | 2002 Jan |
|
| Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. | 2002 Mar |
|
| 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.
| Substance Class |
Chemical
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INTRAVENOUS ADMINISTRATION
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URINE
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EXCRETED UNCHANGED |
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| Volume of Distribution | PHARMACOKINETIC |
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| Tmax | PHARMACOKINETIC |
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| Biological Half-life | PHARMACOKINETIC |
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