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 2778
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 2778	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 2778	95.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 35 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21290se8-001_tracleer_lbl.pdf	Primary		Approved 8429	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
Influence of several methodological procedures utilized to obtain in vitro vascular preparations on endothelial activity.	2001	11824475
Current management of primary pulmonary hypertension.	2001	11708765
Pharmacological regulation of postischemic sinusoidal diameters in rats--a new approach for reducing hepatic ischemia/reperfusion injury.	2001	11564912
Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat.	2001 Dec	11903325
Small bowel review: diseases of the small intestine.	2001 Dec	11768246
Pulmonary hypertension associated with COPD.	2001 Dec	11737906
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	11729239
Role of endogenous endothelin on coronary reflow after cardioplegic arrest.	2001 Dec	11726892
Endothelin antagonist reduces hemodynamic responses to vasopressin in DOCA-salt hypertension.	2001 Dec	11709418
Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat.	2001 Dec	11704565
Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats.	2001 Dec 7	11740953
New pharmacological strategies for the treatment of heart failure.	2001 Jul	11757792
[Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study].	2001 Nov	11826707
Rationale and perspective of endothelin-1 antagonism in acute heart failure.	2001 Nov	11811379
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 decreases glutamate uptake in primary cultured rat astrocytes.	2001 Nov	11600412
Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane.	2001 Nov-Dec	11740152
Endothelin receptor blockade and nitric oxide bioactivity.	2001 Oct	11715916
Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor-no pathway.	2001 Oct	11597932
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
Endothelin receptor blockade in congestive heart failure.	2001 Oct 30	11684644
Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.	2001 Oct 6	11597664
Endothelin-receptor antagonists in pulmonary hypertension.	2001 Oct 6	11597660
Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001.	2001 Oct 9	11591605
Endothelin involvement in respiratory centre activity.	2001 Sep	11728166
Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats.	2001 Sep	11566958
Growth factors in idiopathic pulmonary fibrosis: relative roles.	2002	11806848
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
Medical management of primary pulmonary hypertension.	2002 Feb	11829729
Endothelin antagonists and heart failure.	2002 Feb	11790297
Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis.	2002 Feb 20	11849873
Human endothelin subtype A receptor enhancement during tissue culture via de novo transcription.	2002 Jan	11844243
Direct left ventricular wall stretch activates GATA4 binding in perfused rat heart: involvement of autocrine/paracrine pathways.	2002 Jan	11810204
Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure.	2002 Jan	11772977
Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins.	2002 Jan	11744810
Naftidrofuryl exerts antiserotonergic but no endothelin-receptor blocking effects in AS4.1 cells, juxtaglomerular cells and isolated perfused rat kidneys.	2002 Jan	11743222
[The effects of endothelin blockade on renal expression of angiotensin II type 1 receptor in diabetic hypertensive rats].	2002 Jan 10	11953118
[Physical endurance improves markedly. New therapy approach in pulmonary hypertension].	2002 Jan 17	11847889
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
Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist.	2002 Mar	11865964
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 [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 MONOHYDRATE

Common Name

English

BOSENTAN HYDRATE

Common Name

English

RO-47-0203/029

Code

English

Classification Tree Code System Code

NDF-RT

N0000175581