You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameMacitentan
Accession NumberDB08932
TypeSmall Molecule
GroupsApproved
Description

Macitentan was approved in October 2013. It is indicated for patients with pulmonary arterial hypertension, and is marketed under the brand name Opsumit. Macitentan is an antagonist/blocker of endothelin receptors on blood vessels and smooth muscle, and, thus, blocks the stimulation of vasculature hypertrophy, inflammation, fibrosis, proliferation, and vasoconstriction. Similar to all drugs acting on the renin-angiotensin system, macitentan is associated with embryo and fetal toxicity, so it should not be used in pregnancy and has special precautions that must be followed for all females of child-bearing age.

Structure
Thumb
Synonyms
Macitentanum
External Identifiers
  • ACT 064992
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Opsumittablet, film coated10 mg/1oralActelion Pharmaceuticals US, Inc.2013-10-01Not applicableUs
Opsumittablet10 mgoralActelion Pharmaceuticals Ltd2014-01-15Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIZ9K9Y9WMVL
CAS number441798-33-0
WeightAverage: 588.273
Monoisotopic: 585.963349142
Chemical FormulaC19H20Br2N6O4S
InChI KeyJGCMEBMXRHSZKX-UHFFFAOYSA-N
InChI
InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)
IUPAC Name
{[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl)amine
SMILES
CCCNS(=O)(=O)NC1=C(C(OCCOC2=NC=C(Br)C=N2)=NC=N1)C1=CC=C(Br)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpyrimidines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyrimidine ring through a CC or CN bond. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentPhenylpyrimidines
Alternative Parents
Substituents
  • 5-phenylpyrimidine
  • Halopyrimidine
  • Halobenzene
  • Bromobenzene
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Sulfuric acid diamide
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl bromide
  • Heteroaromatic compound
  • Organic sulfuric acid or derivatives
  • Azacycle
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organobromide
  • Organohalogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationMacitentan is indicated for patients with pulmonary arterial hypertension.
PharmacodynamicsMacitentan blocks simulators of hypertrophy, inflammation, fibrosis, proliferation, and vasoconstriction.
Mechanism of actionMacitentan is an antagonist/blocker of endothelin receptors. Endothelin receptors are found in the endothelial cells of blood vessels and smooth muscle. Macitentan binds to the receptors, endothelin A and B (ETA and ETB), which prevents the agonist endothelin -1 (ET-1) from binding and stimulating the ETA and ETB receptors.
Related Articles
AbsorptionMacitentan is administered orally, and it take about 8 hours for maximum plasma concentrations to be reached.
Volume of distribution

Macitentan has a volume of distribution of 50L.

Protein bindingMacitentan is >99% bound to plasma proteins, which are mainly albumin
Metabolism

Macitentan is metabolised to an active metabolite by CYP 3A4 (major) and CYP 2C19 (minor).

Route of eliminationEliminated 50% through urine and 24% through feces.
Half lifeThe half life of macitentan is 16 hours, and the half life of it's active metabolite is 48 hours.
Clearance

Clearance data was not found.

ToxicityMacitentan has a black box warning of embryo-fetal toxicity. Special precautions must be taken for all females of child-bearing age, and women who are pregnant must not be given macitentan.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral10 mg
Tablet, film coatedoral10 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7094781 No2002-10-122022-10-12Us
US8268847 No2009-04-182029-04-18Us
US8367685 No2008-10-042028-10-04Us
US9265762 No2007-05-292027-05-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityNot water solubleNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00668 mg/mLALOGPS
logP3.05ALOGPS
logP3.69ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)7.76ChemAxon
pKa (Strongest Basic)2.26ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area128.22 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity126.98 m3·mol-1ChemAxon
Polarizability50.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. Pubmed

General References
  1. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. [PubMed:22862294 ]
External Links
ATC CodesC02KX04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (836 KB)
MSDSDownload (105 KB)
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of MACITENTAN can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of MACITENTAN can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of MACITENTAN can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of MACITENTAN can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of MACITENTAN can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of MACITENTAN can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of MACITENTAN can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of MACITENTAN can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of MACITENTAN can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of MACITENTAN can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of MACITENTAN can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of MACITENTAN can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of MACITENTAN can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of MACITENTAN can be decreased when it is combined with Deferasirox.
EnzalutamideThe serum concentration of MACITENTAN can be decreased when it is combined with Enzalutamide.
FluconazoleThe metabolism of MACITENTAN can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of MACITENTAN can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of MACITENTAN can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of MACITENTAN can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of MACITENTAN can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of MACITENTAN can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of MACITENTAN can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of MACITENTAN can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of MACITENTAN can be increased when it is combined with Ketoconazole.
LuliconazoleThe serum concentration of MACITENTAN can be increased when it is combined with Luliconazole.
MifepristoneThe serum concentration of MACITENTAN can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of MACITENTAN can be decreased when it is combined with Mitotane.
NefazodoneThe serum concentration of MACITENTAN can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of MACITENTAN can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of MACITENTAN can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of MACITENTAN can be increased when it is combined with Palbociclib.
PhenobarbitalThe serum concentration of MACITENTAN can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of MACITENTAN can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of MACITENTAN can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of MACITENTAN can be decreased when it is combined with Primidone.
RifabutinThe serum concentration of MACITENTAN can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of MACITENTAN can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of MACITENTAN can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of MACITENTAN can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of MACITENTAN can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of MACITENTAN can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of MACITENTAN can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of MACITENTAN can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of MACITENTAN can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of MACITENTAN can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of MACITENTAN can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of MACITENTAN can be decreased when it is combined with Tocilizumab.
VoriconazoleThe serum concentration of MACITENTAN can be increased when it is combined with Voriconazole.
Food Interactions
  • Can be taken with or without food.

Targets

Kind
Protein
Organism
Human
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: ET1 > ET2 >> ET3.
Gene Name:
EDNRA
Uniprot ID:
P25101
Molecular Weight:
48721.76 Da
References
  1. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. [PubMed:22862294 ]
  2. Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J: Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012 Sep;42(9):901-10. doi: 10.3109/00498254.2012.664665. Epub 2012 Mar 30. [PubMed:22458347 ]
  3. Dingemanse J, Sidharta PN, Maddrey WC, Rubin LJ, Mickail H: Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2014 Mar;13(3):391-405. doi: 10.1517/14740338.2014.859674. Epub 2013 Nov 22. [PubMed:24261583 ]
Kind
Protein
Organism
Human
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
Molecular Weight:
49643.255 Da
References
  1. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. [PubMed:22862294 ]
  2. Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J: Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012 Sep;42(9):901-10. doi: 10.3109/00498254.2012.664665. Epub 2012 Mar 30. [PubMed:22458347 ]
  3. Dingemanse J, Sidharta PN, Maddrey WC, Rubin LJ, Mickail H: Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2014 Mar;13(3):391-405. doi: 10.1517/14740338.2014.859674. Epub 2013 Nov 22. [PubMed:24261583 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. FDA label
  2. Lexicomp
Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
References
  1. FDA label.
  2. Lexicomp.

Carriers

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
binder
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
References
  1. FDA label
Comments
comments powered by Disqus
Drug created on December 29, 2013 11:30 / Updated on May 29, 2016 02:20