Identification

Name
Macitentan
Accession Number
DB08932
Type
Small Molecule
Groups
Approved
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 IDs
ACT 064992 / ACT-064992
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OpsumitTablet10 mgOralActelion2014-01-15Not applicableCanada
OpsumitTablet, film coated10 mg/1OralActelion2013-11-04Not applicableUs
Categories
UNII
Z9K9Y9WMVL
CAS number
441798-33-0
Weight
Average: 588.273
Monoisotopic: 585.963349142
Chemical Formula
C19H20Br2N6O4S
InChI Key
JGCMEBMXRHSZKX-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

Pharmacology

Indication

Macitentan is indicated for patients with pulmonary arterial hypertension.

Associated Conditions
Pharmacodynamics

Macitentan blocks simulators of hypertrophy, inflammation, fibrosis, proliferation, and vasoconstriction.

Mechanism of action

Macitentan 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.

TargetActionsOrganism
AEndothelin-1 receptor
antagonist
Human
AEndothelin B receptor
antagonist
Human
Absorption

Macitentan 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 binding

Macitentan 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 elimination

Eliminated 50% through urine and 24% through feces.

Half life

The 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.

Toxicity

Macitentan 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Macitentan.
AbirateroneThe metabolism of Macitentan can be decreased when combined with Abiraterone.
AcebutololAcebutolol may increase the hypotensive activities of Macitentan.
AcemetacinThe therapeutic efficacy of Macitentan can be decreased when used in combination with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Macitentan which could result in a higher serum level.
Acetyl sulfisoxazoleThe metabolism of Macitentan can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe therapeutic efficacy of Macitentan can be decreased when used in combination with Acetylsalicylic acid.
AlbendazoleThe metabolism of Macitentan can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Macitentan.
AlfuzosinAlfuzosin may increase the hypotensive activities of Macitentan.
Food Interactions
  • Can be taken with or without food.

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
KEGG Drug
D10135
PubChem Compound
16004692
PubChem Substance
175427162
ChemSpider
13134960
BindingDB
50395626
ChEBI
76607
ChEMBL
CHEMBL2103873
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Macitentan
ATC Codes
C02KX04 — Macitentan
AHFS Codes
  • 48:48.00 — Vasodilating Agents
FDA label
Download (836 KB)
MSDS
Download (105 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers2
1CompletedOtherHealthy Volunteers3
1Enrolling by InvitationOtherPulmonary Hypertension (PH) / Sickle Cell Disorders1
1TerminatedTreatmentGlioblastomas2
2Active Not RecruitingTreatmentChronic Thromboembolic Pulmonary Hypertension / Chronic Thromboembolic Pulmonary Hypertension (CTEPH)1
2CompletedTreatmentChronic Thromboembolic Pulmonary Hypertension / Chronic Thromboembolic Pulmonary Hypertension (CTEPH)1
2CompletedTreatmentIdiopathic Pulmonary Fibrosis (IPF)1
2CompletedTreatmentPulmonary Hypertension (PH)1
2RecruitingTreatmentHeart Failure With Preserved Ejection Fraction (HFpEF)1
2RecruitingTreatmentPulmonary Hypertension (PH)1
2WithdrawnTreatmentIdiopathic Pulmonary Fibrosis (IPF)1
3Active Not RecruitingTreatmentPulmonary Arterial Hypertension (PAH)3
3CompletedTreatmentPulmonary Arterial Hypertension (PAH)2
3CompletedTreatmentSclerosis, Progressive Systemic / Ulcers1
3Enrolling by InvitationTreatmentPulmonary Arterial Hypertension (PAH)1
3RecruitingTreatmentCongenital Heart Disease (CHD)1
3RecruitingTreatmentPulmonary Arterial Hypertension (PAH)2
3TerminatedTreatmentDigital Ulcers / Sclerosis, Progressive Systemic / Ulcers1
3TerminatedTreatmentPulmonary Arterial Hypertension (PAH)3
4Active Not RecruitingTreatmentPortopulmonary Hypertension1
4Active Not RecruitingTreatmentPulmonary Arterial Hypertension (PAH)3
4Not Yet RecruitingTreatmentLung Transplant Rejection1
Not AvailableRecruitingNot AvailablePulmonary Arterial Hypertension (PAH)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral10 mg
Tablet, film coatedOral10 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8268847No2009-04-182029-04-18Us
US8367685No2008-10-042028-10-04Us
US9265762No2007-05-292027-05-29Us
US7094781No2002-10-122022-10-12Us

Properties

State
Solid
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. 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
Halopyrimidines
Alternative Parents
Bromobenzenes / Alkyl aryl ethers / Sulfuric acid diamides / Imidolactams / Aryl bromides / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organobromides
show 2 more
Substituents
Alkyl aryl ether / Bromobenzene / Halobenzene / Halopyrimidine / Aryl bromide / Aryl halide / Monocyclic benzene moiety / Imidolactam / Benzenoid / Sulfuric acid diamide
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organobromine compound, aromatic ether, pyrimidines, ring assembly, sulfamides (CHEBI:76607)

Targets

Details
1. Endothelin-1 receptor
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:...
Gene Name
EDNRA
Uniprot ID
P25101
Uniprot Name
Endothelin-1 receptor
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]
Details
2. Endothelin B receptor
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
Uniprot Name
Endothelin B receptor
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da

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 colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Drug created on December 29, 2013 11:30 / Updated on September 23, 2018 19:37