BOSENTAN

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

Structure Search

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021290s012lbl.pdf | https://www.drugbank.ca/drugs/DB00559 | https://www.ncbi.nlm.nih.gov/pubmed/10353441

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	Potency
Endothelin receptor, ET-A/ET-B 3 Target ID: CHEMBL2096678 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021290s012lbl.pdf	Antagonist 2849
Endothelin receptor ET-A 22 Target ID: CHEMBL4566 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10353441 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021290s012lbl.pdf	Antagonist 2849	4.7 nM [Ki]
Endothelin receptor ET-B 11 Target ID: CHEMBL1785 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10353441 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021290s012lbl.pdf	Antagonist 2849	95.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 36 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21290se8-001_tracleer_lbl.pdf	Primary		Approved 8583	TRACLEER Approved Use Tracleer 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 Date 2001

PubMed

Title	Date	PubMed
Current management of primary pulmonary hypertension.	2001	11708765
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	11505783
The loop diuretic torasemide interferes with endothelin-1 actions in the aorta of hypertensive rats.	2001	11369815
Chronic bosentan treatment improves renal artery vascular function in diabetes.	2001 Apr	11330884
The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions.	2001 Apr	11309550
Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1.	2001 Apr	11304520
Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.	2001 Apr	11300660
Improvement of respiratory function by bosentan during endotoxic shock in the pig.	2001 Aug	11545627
Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat.	2001 Dec	11903325
Pulmonary hypertension associated with COPD.	2001 Dec	11737906
Endothelin antagonist reduces hemodynamic responses to vasopressin in DOCA-salt hypertension.	2001 Dec	11709418
Endothelin and heart failure.	2001 Dec	11447308
Hemodynamic effects of bosentan in patients with chronic heart failure.	2001 Dec	11447307
Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats.	2001 Dec 7	11740953
Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo.	2001 Feb	11230293
Important role for endothelins in acute hepatic ischemia/reperfusion injury.	2001 Jan-Feb	11297059
Long-term endothelin receptor blockade improves cardiovascular function in diabetes.	2001 Jul	11465653
Endothelin mediates some of the renal actions of acutely administered angiotensin II.	2001 Jul	11463769
Effects of the endothelin receptor antagonist Bosentan on ischaemia/reperfusion injury in rat skeletal muscle.	2001 Jul 13	11470261
Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure.	2001 Jul 31	11479261
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	11459133
Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 caused by serogroup A streptococci and prolongs survival in rat peritoneal sepsis.	2001 Jun	11386616
Update in pharmacologic treatment of hypertension.	2001 May	11407110
Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future?	2001 May	11345356
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	11343419
Neurogenic inflammation in the context of migraine.	2001 May 1	11301492
Acute endothelin a receptor blockade in heart failure.	2001 May 8	11342484
[Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study].	2001 Nov	11826707
Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock.	2001 Nov	11736680
Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1.	2001 Nov	11696450
Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane.	2001 Nov-Dec	11740152
Endothelin mediates phospholipase C stimulation in the proximal tubule during initiation of compensatory renal growth in adult rats.	2001 Oct	11593498
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	11585441
Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.	2001 Oct 6	11597664
Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001.	2001 Oct 9	11591605
Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats.	2001 Sep	11566958
Endogenous endothelins mediate increased acidification in remnant kidneys.	2001 Sep	11518775
In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide.	2002 Apr	11956508
Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes.	2002 Apr	11910307
Bosentan (Tracleer) for pulmonary arterial hypertension.	2002 Apr 1	11941267
Tracleer. Tablets ease symptoms of rare lung disorder.	2002 Feb	11924160
Human endothelin subtype A receptor enhancement during tissue culture via de novo transcription.	2002 Jan	11844243
Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure.	2002 Jan	11772977
[The effects of endothelin blockade on renal expression of angiotensin II type 1 receptor in diabetic hypertensive rats].	2002 Jan 10	11953118
Tracleer (bosentan).	2002 Jan-Feb	11821645
[Bosentan in pulmonary hypertension].	2002 Mar	11925765
Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure.	2002 Mar	11922906
Bosentan enters market with risk management program.	2002 Mar 15	11908242
Treatment of primary pulmonary hypertension -- the next generation.	2002 Mar 21	11907295
Bosentan therapy for pulmonary arterial hypertension.	2002 Mar 21	11907289

Patents

Sample Use Guides

In Vivo Use Guide

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

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.

Name

Type

Language

BOSENTAN

Official Name

English

BOSENTAN MONOHYDRATE

Preferred Name

English

BOSENTAN [USP-RS]

Common Name

English

BOSENTAN MONOHYDRATE [MI]

Common Name

English

RO-47-0203-029

Code

English

P-TERT-BUTYL-N-(6-(2-HYDROXYETHOXY)-5-(O-METHOXYPHENOXY)-2-(2-PYRIMIDINYL)-4-PYRIMIDINYL)BENZENESULFONAMIDE MONOHYDRATE

Common Name

English

BOSENTAN [USAN]

Common Name

English

BOSENTAN MONOHYDRATE [EMA EPAR]

Common Name

English

RO 47-0203/029

Code

English

RO-470203029

Code

English

TRACLEER

Brand Name

English

BENZENESULFONAMIDE, 4-(1,1-DIMETHYLETHYL)-N-(6-(2-HYDROXYETHOXY)-5-(2-METHOXYPHENOXY)(2,2'BIPYRIMIDIN)-4-YL)-, MONOHYDRATE

Systematic Name

English

BOSENTAN [VANDF]

Common Name

English

BOSENTAN HYDRATE [JAN]

Common Name

English

BOSENTAN [ORANGE BOOK]

Common Name

English

Bosentan monohydrate [WHO-DD]

Common Name

English

BOSENTAN HYDRATE

Common Name

English

RO-47-0203/029

Code

English

Classification Tree Code System Code

NDF-RT

N0000175581