BOSENTAN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C27H29N5O6S.H2O
Molecular Weight	569.6315
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(C)c1ccc(cc1)S(=O)(=O)Nc2c(c(nc(-c3ncccn3)n2)OCCO)Oc4ccccc4OC.O

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

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

Molecular Formula	C27H29N5O6S
Molecular Weight	551.6162
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 2575
Endothelin receptor ET-A 19 Target ID: CHEMBL4566 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10353441 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021290s012lbl.pdf	Antagonist 2575	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 2575	95.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 34 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21290se8-001_tracleer_lbl.pdf	Primary		Approved 8043	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 1.00621438E12

PubMed

Title	Date	PubMed
Endothelin antagonism with bosentan: a review of potential applications.	1999 Apr	10353441
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
Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation.	2001 Apr	11238005
The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure.	2001 Aug	11532543
Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation.	2001 Aug	11515898
Report From the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001.	2001 Aug 28	11526948
Pulmonary hypertension associated with COPD.	2001 Dec	11737906
Endothelin and heart failure.	2001 Dec	11447308
Hemodynamic effects of bosentan in patients with chronic heart failure.	2001 Dec	11447307
Endothelin antagonism in experimental ischemic heart failure: hemodynamic, structural and neurohumoral effects.	2001 Dec	11447304
Therapeutic role of bosentan in hypertension: lessons from the model of perinephritic hypertension.	2001 Dec	11447300
Role of endothelin and isoprostanes in slow pressor responses to angiotensin II.	2001 Feb	11230326
Regression of renal vascular fibrosis by endothelin receptor antagonism.	2001 Feb	11230324
Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo.	2001 Feb	11230293
Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts.	2001 Jan	11156582
Endothelin receptor antagonist prevents parathyroid cell proliferation of low calcium diet-induced hyperparathyroidism in rats.	2001 Jan	11145604
Endothelin receptor blockade improves endothelial function in human internal mammary arteries.	2001 Jan	11121806
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
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	11444506
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
The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock.	2001 Mar 2	11239929
Update in pharmacologic treatment of hypertension.	2001 May	11407110
Blockade of the renin-angiotensin and endothelin systems on progressive renal injury.	2001 May	11358955
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 mediates phospholipase C stimulation in the proximal tubule during initiation of compensatory renal growth in adult rats.	2001 Oct	11593498
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
Growth factors in idiopathic pulmonary fibrosis: relative roles.	2002	11806848
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
Endothelin antagonists and heart failure.	2002 Feb	11790297
Human endothelin subtype A receptor enhancement during tissue culture via de novo transcription.	2002 Jan	11844243
Naftidrofuryl exerts antiserotonergic but no endothelin-receptor blocking effects in AS4.1 cells, juxtaglomerular cells and isolated perfused rat kidneys.	2002 Jan	11743222
[Bosentan in pulmonary hypertension].	2002 Mar	11925765
Bosentan enters market with risk management program.	2002 Mar 15	11908242

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.

Substance Class	Chemical Created by `admin` on `Sat Jun 26 02:56:55 UTC 2021` Edited by `admin` on `Sat Jun 26 02:56:55 UTC 2021`
Record UNII	Q326023R30
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BOSENTAN

Official Name

English

BOSENTAN [USP-RS]

Common Name

English

BOSENTAN MONOHYDRATE [MI]

Common Name

English

BOSENTAN MONOHYDRATE [WHO-DD]

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

Common Name

English

BOSENTAN HYDRATE

Common Name

English

RO-47-0203/029

Code

English

Classification Tree Code System Code

NDF-RT

N0000175581