Identification

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Name
Bosentan
Accession Number
DB00559  (APRD00829)
Type
Small Molecule
Groups
Approved, Investigational
Description

Bosentan is a dual endothelin receptor antagonist marketed under the trade name Tracleer by Actelion Pharmaceuticals. 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.

Structure
Thumb
Synonyms
  • 4-(1,1-Dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-(2,2'-bipyrimidin)-4-yl) benzenesulfornamide
  • bosentán
  • Bosentan
  • bosentan anhydrous
  • bosentanum
  • p-tert-Butyl-N-(6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl)benzenesulfonamide
Product Ingredients
IngredientUNIICASInChI Key
Bosentan monohydrateQ326023R30157212-55-0SXTRWVVIEPWAKM-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Act BosentanTabletOralActavis Pharma Company2012-06-052018-04-25Canada
Act BosentanTabletOralActavis Pharma Company2012-06-052018-04-25Canada
BosentanTablet125 mgOralPanda Pharmaceuticals Inc.Not applicableNot applicableCanada
BosentanTablet62.5 mgOralPanda Pharmaceuticals Inc.Not applicableNot applicableCanada
BosentanTablet125 mgOralActelionNot applicableNot applicableCanada
BosentanTablet62.5 mgOralActelionNot applicableNot applicableCanada
Bosentan TabletsTabletOralAccord Healthcare Inc2014-11-132015-06-02Canada
StayveerTablet, film coated62.5 mgOralMarklas Nederlands Bv2013-06-24Not applicableEu
StayveerTablet, film coated125 mgOralMarklas Nederlands Bv2013-06-24Not applicableEu
StayveerTablet, film coated62.5 mgOralMarklas Nederlands Bv2013-06-24Not applicableEu
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Accel-bosentanTabletOralAccel Pharma IncNot applicableNot applicableCanada
Apo-bosentanTabletOralApotex Corporation2017-07-14Not applicableCanada
Apo-bosentanTabletOralApotex Corporation2017-07-14Not applicableCanada
Bio-bosentanTabletOralBiomed Pharma2017-08-23Not applicableCanada
Bio-bosentanTabletOralBiomed Pharma2017-08-23Not applicableCanada
BosentanTablet, film coated62.5 mg/1OralActavis Pharma, Inc.2019-06-19Not applicableUs
BosentanTablet62.5 mg/1OralLupin Pharmaceuticals, Inc.2019-04-26Not applicableUs
BosentanTablet, coated62.5 mg/1OralZydus Pharmaceuticals (USA) Inc.2019-05-01Not applicableUs
BosentanTablet, film coated62.5 mg/1OralPar Pharmaceutical, Inc.2019-04-29Not applicableUs
BosentanTablet, film coated125 mg/1OralCoTherix, Inc.2019-06-03Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
XUL93R30K2
CAS number
147536-97-8
Weight
Average: 551.614
Monoisotopic: 551.183854375
Chemical Formula
C27H29N5O6S
InChI Key
GJPICJJJRGTNOD-UHFFFAOYSA-N
InChI
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)
IUPAC Name
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
SMILES
COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)N=C(N=C1OCCO)C1=NC=CC=N1

Pharmacology

Indication

Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).

Associated Conditions
Pharmacodynamics

Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Mechanism of action

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ETA receptors than ETB receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB.

TargetActionsOrganism
AEndothelin-1 receptor
antagonist
Humans
AEndothelin B receptor
antagonist
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Absolute bioavailability is approximately 50% and food does not affect absorption.

Volume of distribution
  • 18 L
Protein binding

Greater than 98% to plasma proteins, mainly albumin.

Metabolism

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

Route of elimination

Bosentan is eliminated by biliary excretion following metabolism in the liver.

Half life

Terminal elimination half-life is about 5 hours in healthy adult subjects.

Clearance
  • 4 L/h [patients with pulmonary arterial hypertension]
Toxicity

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Bosentan.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Bosentan.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may decrease the antihypertensive activities of Bosentan.
1-benzylimidazole1-benzylimidazole may decrease the antihypertensive activities of Bosentan.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Bosentan.
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the antihypertensive activities of Bosentan.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may decrease the antihypertensive activities of Bosentan.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the antihypertensive activities of Bosentan.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Bosentan.
4-Methoxyamphetamine4-Methoxyamphetamine may decrease the antihypertensive activities of Bosentan.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
  • Take without regard to meals.

References

Synthesis Reference

Maurizio TADDEI, Diletta Naldini, Pietro Allegrini, Gabriele Razzetti, Simone Mantegazza, "Process for the Preparation of Bosentan." U.S. Patent US20090156811, issued June 18, 2009.

US20090156811
General References
Not Available
External Links
Human Metabolome Database
HMDB0014699
KEGG Drug
D01227
PubChem Compound
104865
PubChem Substance
46507154
ChemSpider
94651
BindingDB
50061101
ChEBI
51450
ChEMBL
CHEMBL957
Therapeutic Targets Database
DNC000341
PharmGKB
PA10034
HET
K86
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Bosentan
ATC Codes
G01AE10 — Combinations of sulfonamidesC02KX01 — Bosentan
AHFS Codes
  • 48:48.00 — Vasodilating Agents
PDB Entries
5xpr
FDA label
Download (424 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic SciencePulmonary Arterial Hypertension (PAH) / Vasoconstriction / Vasodilation1
1CompletedBasic ScienceBioequivalence1
1CompletedTreatmentAltitude / Pulmonary Hypertension (PH)1
1CompletedTreatmentBioequivalence Study / Pulmonary Arterial Hypertension (PAH)1
1CompletedTreatmentBlood Flow Velocity / Glaucoma1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHigh Blood Pressure (Hypertension)1
1CompletedTreatmentHypoxia-Induced Pulmonary Artery Hypertension1
1Not Yet RecruitingTreatmentDiabetes Mellitus (DM)1
1Unknown StatusTreatmentHealthy Volunteers1
1, 2TerminatedTreatmentSystemic Sclerosis (Scleroderma)1
1, 2Unknown StatusTreatmentChildhood rheumatoid fever / Congestive Heart Failure / Mitral Valve Stenosis / Pulmonary Hypertension Secondary1
2Active Not RecruitingTreatmentCongenital Heart Disease (CHD) / Pulmonary Arterial Hypertension (PAH)1
2CompletedTreatmentDefect, Congenital Heart / Functional Single Ventricle1
2CompletedTreatmentHand Functionality / Scleroderma, Systemic / Skin Fibrosis1
2CompletedTreatmentHigh Blood Pressure (Hypertension) / Obstructive Sleep Apnea (OSA)1
2CompletedTreatmentHypoplastic Left Heart Syndrome (HLHS) / Other Specified Congenital Anomalies of Heart / Tricuspid Atresia1
2CompletedTreatmentMelanoma1
2CompletedTreatmentPort-wine Stains (PWS)1
2CompletedTreatmentScleroderma Renal Crisis1
2CompletedTreatmentType 2 Diabetes Mellitus1
2TerminatedTreatmentAsthma1
2TerminatedTreatmentHepatopulmonary Syndrome / Liver Cirrhosis1
2TerminatedTreatmentPulmonary Hypertension (PH) / Sarcoidosis1
2TerminatedTreatmentPulmonary Hypertension (PH) / Scleroderma, Systemic1
2Unknown StatusTreatmentAsthma1
2Unknown StatusTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2, 3CompletedBasic SciencePulmonary Hypertension (PH)1
2, 3CompletedTreatmentIdiopathic Pulmonary Fibrosis (IPF)1
2, 3CompletedTreatmentInterstitial Lung Disease (ILD) / Scleroderma1
2, 3CompletedTreatmentPulmonary Arterial Hypertension (PAH) / Sarcoidosis1
2, 3CompletedTreatmentPulmonary Fibrosis / Scleroderma, Systemic1
3CompletedTreatmentChronic Thromboembolic Pulmonary Hypertension1
3CompletedTreatmentDigital Ulcers / Scleroderma / Sclerosis, Progressive Systemic1
3CompletedTreatmentDigital Ulcers / Sclerosis, Progressive Systemic1
3CompletedTreatmentEisenmenger's Syndrome1
3CompletedTreatmentHeart Failure, Diastolic / Pulmonary Hypertension (PH)1
3CompletedTreatmentHeart Septal Defects, Atrial1
3CompletedTreatmentIdiopathic Pulmonary Fibrosis (IPF)2
3CompletedTreatmentPulmonary Arterial Hypertension (PAH)2
3CompletedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)2
3CompletedTreatmentPulmonary Hypertension (PH)2
3Not Yet RecruitingTreatmentBlindness and Low Vision / Giant Cells Arteritis1
3Not Yet RecruitingTreatmentPediatric Hypertension1
3RecruitingTreatmentIschemic Optic Neuropathy1
3TerminatedTreatmentPersistent Pulmonary Hypertension of the Newborn1
3TerminatedTreatmentPulmonary Hypertension (PH)3
3TerminatedTreatmentPulmonary Hypertension (PH) / Sickle Cell Disorders1
3TerminatedTreatmentType 2 Diabetes Mellitus1
3Unknown StatusTreatmentConnective Tissue Diseases / Pulmonary Hypertension (PH)1
3Unknown StatusTreatmentPulmonary Arterial Hypertension (PAH)1
4Active Not RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
4CompletedBasic ScienceType 2 Diabetes Mellitus1
4CompletedSupportive CareType 2 Diabetes Mellitus1
4CompletedTreatmentDigital Ulcers / Sclerosis, Progressive Systemic1
4CompletedTreatmentEisenmenger's Syndrome1
4CompletedTreatmentPulmonary Arterial Hypertension (PAH)4
4CompletedTreatmentPulmonary Arterial Hypertension Related to Eisenmenger Physiology1
4CompletedTreatmentPulmonary Hypertension (PH)2
4CompletedTreatmentScleroderma, Systemic1
4RecruitingTreatmentAssociated Pulmonary Arterial Hypertension1
4TerminatedNot AvailablePulmonary Hypertension (PH)1
4TerminatedTreatmentHigh Blood Pressure (Hypertension)1
4TerminatedTreatmentPulmonary Hypertension (PH)1
4Unknown StatusTreatmentIdiopathic Pulmonary Fibrosis (IPF) / Interstitial Lung Disease (ILD) / Nonspecific Interstitial Pneumonia / Pulmonary Hypertension (PH)1
4Unknown StatusTreatmentPulmonary Hypertension Secondary to Lung Disease and/or Hypoxia1
4WithdrawnTreatmentIdiopathic Pulmonary Fibrosis (IPF) / Pulmonary Arterial Hypertension (PAH)1
Not AvailableCompletedNot AvailableDigital Ulcer / Scleroderma / Systematic Sclerosis1
Not AvailableCompletedNot AvailablePulmonary Arterial Hypertension (PAH)2
Not AvailableCompletedNot AvailableThromboangiitis Obliterans1
Not AvailableCompletedNot AvailableVA Drug Interactions [VA Drug Interaction]1
Not AvailableCompletedSupportive CareCongenital Heart Disease (CHD)1
Not AvailableCompletedTreatmentPeripheral Arterial Disease (PAD)1
Not AvailableCompletedTreatmentPulmonary Arterial Hypertension (PAH)1
Not AvailableCompletedTreatmentPulmonary Hypertension (PH) / Sclerosis, Progressive Systemic1
Not AvailableRecruitingNot AvailableAcute Bacterial Exacerbation of Chronic Bronchitis (ABECB) / Acute Bacterial Sinusitis (ABS) / Acute Decompensated Heart Failure (ADHF) / Acute Pyelonephritis / Adenovirus / Adjunct to general anesthesia therapy / Adrenal Insufficiency / Airway Swelling / Anaesthesia therapy / Anxiety / Anxiolysis / Autism, Early Infantile / Autistic Disorder / Bartonellosis / Benzodiazepine Withdrawal / Benzodiazepines / Bipolar Disorder (BD) / Bloodstream Infections / Bone and Joint Infections / Bradycardia / Brain Swelling / Bronchospasm (rare) / Brucellosis / Cardiac Arrest / Cardiac Dysrhythmia / Central Nervous System Infections / Cholera / Chronic Bacterial Prostatitis / Chronic Kidney Disease (CKD) / Community Acquired Pneumonia (CAP) / Complicated Urinary Tract Infection / Convulsions / Cytomegalovirus Retinitis / Drug hypersensitivity reaction / Early-onset Schizophrenia Spectrum Disorders / Edema / Endocarditis / Epilepsies / Fibrinolytic Bleeding / Flu caused by Influenza / Gastroparesis / Gram-negative Infection / Gynaecological infection / Headache / Heart Failure / Heavy Menstrual Bleeding / Hemophilia / Herpes Simplex Virus / High Blood Pressure (Hypertension) / High Cholesterol / Hospital-acquired bacterial pneumonia / Hyperaldosteronism / Hyperlipidemias / Hypokalaemia / Hypotension / Infantile Hemangiomas / Infection caused by staphylococci / Infection NOS / Inflammatory Conditions / Inflammatory Reaction / Influenza Treatment or Prophylaxis / Inhalational Anthrax (Post-Exposure) / Insomnia / Intra-Abdominal Infections / Life-threatening Fungal Infections / Lower Respiratory Tract Infection (LRTI) / Meningitis, Bacterial / Methicillin Resistant Staphylococcus Aureus (MRSA) / Migraine / Muscle Spasms / Nausea / Neuromuscular Blockade / Neutropenia / Opioid Addiction / Pain / Plague / Pneumonia / Prophylaxis / Psittacosis / Pulmonary Arterial Hypertension (PAH) / Q Fever / Reflux / Relapsing Fever / Rocky Mountain Spotted Fever / Schizophrenic Disorders / Sedation / Seizures / Sepsis / Skeletal Muscle Spasms / Skin and Subcutaneous Tissue Bacterial Infections / Skin Structures and Soft Tissue Infections / Stable Angina (SA) / Thromboprophylaxis / Thrombotic events / Toxic effect of hydrocyanic acid and cyanides / Trachoma / Treatment-resistant Schizophrenia / Tularemia / Typhus Fever / Uncomplicated Skin and Skin Structure Infections / Uncomplicated Urinary Tract Infections / Urinary Tract Infection / Vomiting / Withdrawal1
Not AvailableRecruitingTreatmentCongenital Heart Disease (CHD)1
Not AvailableRecruitingTreatmentCongenital Heart Disease (CHD) / Pulmonary Arterial Hypertension (PAH)1
Not AvailableRecruitingTreatmentHigh Blood Pressure (Hypertension)1
Not AvailableUnknown StatusNot AvailablePAH WHO Group I / Pulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)1
Not AvailableUnknown StatusPreventionRaynaud's Phenomenon / Skin Necrosis1

Pharmacoeconomics

Manufacturers
  • Actelion ltd
Packagers
  • Actelion Pharmaceuticals Inc.
  • Action Pharmaceuticals Ltd.
  • Haupt Pharma
  • Patheon Inc.
Dosage forms
FormRouteStrength
TabletOral125 mg/1
TabletOral62.5 mg/1
Tablet, coatedOral125 mg/1
Tablet, coatedOral62.5 mg/1
Tablet, film coatedOral125 mg/1
Tablet, film coatedOral62.5 mg/1
TabletOral
Tablet, film coatedOral125 mg
Tablet, film coatedOral62.5 mg
TabletOral125 mg
TabletOral62.5 mg
Tablet, for suspensionOral32 mg
Tablet, solubleOral32 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2071193No1998-08-252012-06-12Canada
US5292740No1994-03-082015-11-20Us
US7959945No2011-06-142027-12-28Us
US8309126No2012-11-132026-05-15Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPoorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).Not Available
logP3.7Not Available
Caco2 permeability-5.98ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.00904 mg/mLALOGPS
logP4.18ALOGPS
logP4.94ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)5.8ChemAxon
pKa (Strongest Basic)-0.43ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area145.65 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity166.66 m3·mol-1ChemAxon
Polarizability57.89 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9253
Blood Brain Barrier-0.7419
Caco-2 permeable-0.8956
P-glycoprotein substrateNon-substrate0.5738
P-glycoprotein inhibitor INon-inhibitor0.6175
P-glycoprotein inhibitor IINon-inhibitor0.5092
Renal organic cation transporterNon-inhibitor0.9149
CYP450 2C9 substrateNon-substrate0.5926
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.5132
CYP450 1A2 substrateNon-inhibitor0.7203
CYP450 2C9 inhibitorInhibitor0.518
CYP450 2D6 inhibitorNon-inhibitor0.8755
CYP450 2C19 inhibitorNon-inhibitor0.5219
CYP450 3A4 inhibitorInhibitor0.8407
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.772
Ames testNon AMES toxic0.6147
CarcinogenicityNon-carcinogens0.6515
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2676 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9679
hERG inhibition (predictor II)Non-inhibitor0.572
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udj-0810090000-b97444dff91ec725276d
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-1690040000-c561d9dbb5ed88285519

Taxonomy

Description
This compound belongs to the class of organic compounds known as bipyrimidines and oligopyrimidines. These are organic compounds containing two or more pyrimidine rings directly linked to each other. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Bipyrimidines and oligopyrimidines
Alternative Parents
Diarylethers / Benzenesulfonamides / Phenylpropanes / Benzenesulfonyl compounds / Phenoxy compounds / Anisoles / Methoxybenzenes / Alkyl aryl ethers / Organosulfonamides / Imidolactams
show 8 more
Substituents
Bipyrimidine / Diaryl ether / Benzenesulfonamide / Benzenesulfonyl group / Phenylpropane / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene / Alkyl aryl ether
show 22 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
sulfonamide, pyrimidines, primary alcohol (CHEBI:51450)

Targets

Details
1. Endothelin-1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is:...
Gene Name
EDNRA
Uniprot ID
P25101
Uniprot Name
Endothelin-1 receptor
Molecular Weight
48721.76 Da
References
  1. Albertini M, Lafortuna CL, Ciminaghi B, Mazzola S, Clement MG: Endothelin involvement in respiratory centre activity. Prostaglandins Leukot Essent Fatty Acids. 2001 Sep;65(3):157-63. [PubMed:11728166]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  3. Kiowski W, Sutsch G, Oechslin E, Bertel O: Hemodynamic effects of bosentan in patients with chronic heart failure. Heart Fail Rev. 2001 Dec;6(4):325-34. [PubMed:11447307]
  4. Kramp R, Fourmanoir P, Caron N: Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat. Am J Physiol Renal Physiol. 2001 Dec;281(6):F1132-40. [PubMed:11704565]
  5. Martin C, Held HD, Uhlig S: Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. [PubMed:10961375]
  6. Sihvola RK, Pulkkinen VP, Koskinen PK, Lemstrom KB: Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. J Am Coll Cardiol. 2002 Feb 20;39(4):710-7. [PubMed:11849873]
Details
2. Endothelin B receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Peptide hormone binding
Specific Function
Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name
EDNRB
Uniprot ID
P24530
Uniprot Name
Endothelin B receptor
Molecular Weight
49643.255 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Gardiner SM, Kemp PA, March JE, Bennett T: Effects of bosentan (Ro 47-0203), an ETA-, ETB-receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats. Br J Pharmacol. 1994 Jul;112(3):823-30. [PubMed:7921608]
  3. Gupta SK, Saxena A, Singh U, Arya DS: Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2005 Jul;275(1-2):67-74. [PubMed:16335785]
  4. Marano G, Palazzesi S, Bernucci P, Grigioni M, Formigari R, Ballerini L: ET(A)/ET(B) receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. Life Sci. 1998;63(18):PL259-66. [PubMed:9806221]
  5. Richard V, Kaeffer N, Hogie M, Tron C, Blanc T, Thuillez C: Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. Br J Pharmacol. 1994 Nov;113(3):869-76. [PubMed:7858879]
  6. Said SA, Ammar el SM, Suddek GM: Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res. 2005 Feb;51(2):107-15. [PubMed:15629255]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Dingemanse J, Schaarschmidt D, van Giersbergen PL: Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301. [PubMed:12603176]
  2. Dingemanse J, van Giersbergen PL: Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. [PubMed:15568889]
  3. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  4. FDA table of interactions [Link]
  5. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Matsunaga N, Kaneko N, Staub AY, Nakanishi T, Nunoya K, Imawaka H, Tamai I: Analysis of the Metabolic Pathway of Bosentan and of the Cytotoxicity of Bosentan Metabolites Based on a Quantitative Modeling of Metabolism and Transport in Sandwich-Cultured Human Hepatocytes. Drug Metab Dispos. 2016 Jan;44(1):16-27. doi: 10.1124/dmd.115.067074. Epub 2015 Oct 26. [PubMed:26502773]
  3. Cheng JW: Bosentan. Heart Dis. 2003 Mar-Apr;5(2):161-9. [PubMed:12713683]
  4. van Giersbergen PL, Halabi A, Dingemanse J: Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol. 2002 Jun;53(6):589-95. [PubMed:12047483]
  5. Elshaboury SM, Anderson JR: Ambrisentan for the treatment of pulmonary arterial hypertension: improving outcomes. Patient Prefer Adherence. 2013 May 8;7:401-9. doi: 10.2147/PPA.S30949. Print 2013. [PubMed:23674888]
  6. Bosentan FDA label [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ: The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 Apr;69(4):223-31. [PubMed:11309550]

Drug created on June 13, 2005 07:24 / Updated on November 13, 2019 18:22