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Details

Stereochemistry ACHIRAL
Molecular Formula C19H20Br2N6O4S
Molecular Weight 588.2738
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MACITENTAN

SMILES

CCCNS(=O)(=O)N=c1c(-c2ccc(cc2)Br)c([nH]cn1)OCCOc3ncc(cn3)Br

InChI

InChIKey=JGCMEBMXRHSZKX-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Description
Curator's Comment:: http://www.ncbi.nlm.nih.gov/pubmed/?term=26111581

Macitentan is an orally active, dual endothelin receptor antagonist with tissue targeting properties. Macitentan inhibits both ETA and ETB receptors and prevents them from binding to ET-1. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro. Macitentan is approved in the EU (as monotherapy or combination therapy) for the long-term treatment of pulmonary arterial hypertension (PAH) in adults of WHO functional class II or III, and in the USA for the treatment of PAH (WHO group I) to delay disease progression and reduce hospitalization for PAH.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P25101|||Q16433
Gene ID: 1909
Gene Symbol: EDNRA
Target Organism: Homo sapiens (Human)
0.5 nM [IC50]
Target ID: P24530|||Q8NHM8
Gene ID: 1910
Gene Symbol: EDNRB
Target Organism: Homo sapiens (Human)
391 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
OPSUMIT

Approved Use

Indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced hospitalization for PAH.

Launch Date

1382054400000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
227 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MACITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
178 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
APROCITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
5759 ng × h/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MACITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
19749 ng × h/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
APROCITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
14.1 h
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MACITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
46.7 h
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
APROCITENTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
600 mg single, oral
Highest studied dose
Dose: 600 mg
Route: oral
Route: single
Dose: 600 mg
Sources:
healthy, 19– 49 years
Health Status: healthy
Age Group: 19– 49 years
Sex: M
Sources:
DLT: Headache, Nausea...
Dose limiting toxicities:
Headache (moderate, 5 patients)
Nausea (2 patients)
Vomiting (2 patients)
Sources:
300 mg single, oral
MTD
healthy, 19– 49 years
10 mg 1 times / day steady, oral
Recommended
Dose: 10 mg, 1 times / day
Route: oral
Route: steady
Dose: 10 mg, 1 times / day
Sources:
pregnant, adult
Health Status: pregnant
Age Group: adult
Sex: F
Sources:
Other AEs: Fetal damage...
AEs

AEs

AESignificanceDosePopulation
Nausea 2 patients
DLT
600 mg single, oral
Highest studied dose
Dose: 600 mg
Route: oral
Route: single
Dose: 600 mg
Sources:
healthy, 19– 49 years
Health Status: healthy
Age Group: 19– 49 years
Sex: M
Sources:
Vomiting 2 patients
DLT
600 mg single, oral
Highest studied dose
Dose: 600 mg
Route: oral
Route: single
Dose: 600 mg
Sources:
healthy, 19– 49 years
Health Status: healthy
Age Group: 19– 49 years
Sex: M
Sources:
Headache moderate, 5 patients
DLT
600 mg single, oral
Highest studied dose
Dose: 600 mg
Route: oral
Route: single
Dose: 600 mg
Sources:
healthy, 19– 49 years
Health Status: healthy
Age Group: 19– 49 years
Sex: M
Sources:
Fetal damage
10 mg 1 times / day steady, oral
Recommended
Dose: 10 mg, 1 times / day
Route: oral
Route: steady
Dose: 10 mg, 1 times / day
Sources:
pregnant, adult
Health Status: pregnant
Age Group: adult
Sex: F
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely
no [IC50 14 uM]
no [IC50 6.9 uM]
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no (co-administration study)
Comment: macitentan did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug riociguat or rosuvastatin
Page: 10
unlikely [IC50 18 uM]
unlikely [IC50 19 uM]
yes [EC50 1.1 uM]
yes [IC50 21 uM]
yes [IC50 24 uM]
yes [IC50 5.6 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: ketoconazole increased macitentan Cmax by 1.3-fold and AUC by 2.3-fold; rifampin decreased macitentan expsoure by 80%
Page: 52, 61, 63, 65
minor
minor
minor
no (co-administration study)
Comment: warfarin had no significant impact on the exposure to macitentan
Page: 10
no
no
no
no
no
no
no
no
no
no
no
no (co-administration study)
Comment: cyclosporine-A had no significant impact on the exposure to macitentan
Page: 52, 64
no
no (co-administration study)
Comment: cyclosporine-A had no significant impact on the exposure to macitentan
Page: 52, 64
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist.
2012 Sep 13
Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension.
2015 Aug 15
Patents

Sample Use Guides

The recommended dosage is 10 mg once daily for oral administration.
Route of Administration: Oral
Name Type Language
MACITENTAN
DASH   INN   MI   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
MACITENTAN [VANDF]
Common Name English
MACITENTAN [JAN]
Common Name English
OPSUMIT
Brand Name English
MACITENTAN [ORANGE BOOK]
Common Name English
MACITENTAN [USAN]
Common Name English
ACT 064992
Code English
MACITENTAN [WHO-DD]
Common Name English
MACITENTAN [MI]
Common Name English
N-(5-(4-BROMOPHENYL)-6-(2-((5-BROMOPYRIMIDIN-2-YL)OXY)ETHOXY)PYRIMIDIN-4-YL)-N'-PROPYLSULFAMIDE
Systematic Name English
N-(5-(4-BROMOPHENYL)-6-(2-((5-BROMOPYRIMIDIN-2-YL)OXI)ETHOXY)PYRIMIDIN-4-YL)-N'-PROPYLSULFURIC DIAMIDE
Common Name English
ACT-064992
Code English
SULFAMIDE, N-(5-(4-BROMOPHENYL)-6-(2-((5-BROMO-2-PYRIMIDINYL)OXY)ETHOXY)-4-PYRIMIDINYL)-N'-PROPYL-
Systematic Name English
MACITENTAN [INN]
Common Name English
Classification Tree Code System Code
WHO-ATC C02KX04
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
FDA ORPHAN DRUG 580117
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
EMA ASSESSMENT REPORTS OPSUMIT (AUTHORIZED: HYPERTENSION, PULMONARY)
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
FDA ORPHAN DRUG 282209
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
WHO-VATC QC02KX04
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
FDA ORPHAN DRUG 509615
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
FDA ORPHAN DRUG 574917
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
NDF-RT N0000175581
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
FDA ORPHAN DRUG 279309
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
EU-Orphan Drug EU/3/11/909
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
Code System Code Type Description
INN
9018
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
MERCK INDEX
M6975
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY Merck Index
PUBCHEM
16004692
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
EVMPD
SUB89247
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
CAS
441798-33-0
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
RXCUI
1442132
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY RxNorm
DRUG BANK
DB08932
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
DRUG CENTRAL
4809
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
IUPHAR
7352
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
FDA UNII
Z9K9Y9WMVL
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
EPA CompTox
441798-33-0
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
ChEMBL
CHEMBL2103873
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY
NCI_THESAURUS
C87728
Created by admin on Sat Jun 26 10:29:24 UTC 2021 , Edited by admin on Sat Jun 26 10:29:24 UTC 2021
PRIMARY