Details
Stereochemistry | ACHIRAL |
Molecular Formula | C19H20Br2N6O4S |
Molecular Weight | 588.273 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCNS(=O)(=O)NC1=NC=NC(OCCOC2=NC=C(Br)C=N2)=C1C3=CC=C(Br)C=C3
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)
Molecular Formula | C19H20Br2N6O4S |
Molecular Weight | 588.273 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionCurator's Comment: description was created based on several sources, including
http://www.ncbi.nlm.nih.gov/pubmed/?term=26111581
Curator's Comment: description was created based on several sources, including
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
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: P25101|||Q16433 Gene ID: 1909.0 Gene Symbol: EDNRA Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=26111581 |
0.5 nM [IC50] | ||
Target ID: P24530|||Q8NHM8 Gene ID: 1910.0 Gene Symbol: EDNRB Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=22862294 |
391.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | OPSUMIT Approved UseIndicated 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 Date2013 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
227 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5759 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
14.1 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23568224 |
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
Dose | Population | Adverse events |
---|---|---|
600 mg single, oral Highest studied dose |
healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: |
DLT: Headache, Nausea... Dose limiting toxicities: Headache (moderate, 5 patients) Sources: Nausea (2 patients) Vomiting (2 patients) |
300 mg single, oral MTD Dose: 300 mg Route: oral Route: single Dose: 300 mg Sources: |
healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: |
|
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... Other AEs: Fetal damage Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Nausea | 2 patients DLT |
600 mg single, oral Highest studied dose |
healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: |
Vomiting | 2 patients DLT |
600 mg single, oral Highest studied dose |
healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: |
Headache | moderate, 5 patients DLT |
600 mg single, oral Highest studied dose |
healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 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: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 63, 64 |
likely | |||
Page: 55.0 |
no [IC50 14 uM] | |||
Page: 55.0 |
no [IC50 6.9 uM] | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 63.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 54.0 |
no | |||
Page: 10.0 |
no | no (co-administration study) Comment: macitentan did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug riociguat or rosuvastatin Page: 10.0 |
||
Page: 55.0 |
unlikely [IC50 18 uM] | |||
Page: 55.0 |
unlikely [IC50 19 uM] | |||
Page: 63.0 |
yes [EC50 1.1 uM] | |||
Page: 63.0 |
yes [IC50 21 uM] | |||
Page: 63.0 |
yes [IC50 24 uM] | |||
Page: 63.0 |
yes [IC50 5.6 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 52, 61, 63, 65 |
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 |
||
Page: 51, 52, 61, 63, 64 |
minor | |||
Page: 10.0 |
minor | |||
Page: 10.0 |
minor | no (co-administration study) Comment: warfarin had no significant impact on the exposure to macitentan Page: 10.0 |
||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 10.0 |
no | |||
Page: 7.0 |
no | |||
Page: 52, 64 |
no | no (co-administration study) Comment: cyclosporine-A had no significant impact on the exposure to macitentan Page: 52, 64 |
||
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
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 28.0 |
Substance Class |
Chemical
Created
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admin
on
Edited
Sat Dec 16 17:43:58 GMT 2023
by
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on
Sat Dec 16 17:43:58 GMT 2023
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Record UNII |
Z9K9Y9WMVL
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Validated (UNII)
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WHO-ATC |
C02KX04
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FDA ORPHAN DRUG |
580117
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EMA ASSESSMENT REPORTS |
OPSUMIT (AUTHORIZED: HYPERTENSION, PULMONARY)
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FDA ORPHAN DRUG |
282209
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WHO-VATC |
QC02KX04
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FDA ORPHAN DRUG |
509615
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FDA ORPHAN DRUG |
574917
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NDF-RT |
N0000175581
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FDA ORPHAN DRUG |
279309
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EU-Orphan Drug |
EU/3/11/909
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9018
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m6975
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16004692
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SUB89247
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441798-33-0
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76607
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1442132
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DB08932
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4809
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7352
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Z9K9Y9WMVL
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DTXSID50196063
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100000140050
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CHEMBL2103873
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Macitentan
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YY-66
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Z9K9Y9WMVL
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C87728
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Related Record | Type | Details | ||
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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TARGET -> INHIBITOR |
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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TARGET -> INHIBITOR |
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BINDER->LIGAND |
BINDING
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Related Record | Type | Details | ||
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METABOLITE ACTIVE -> PARENT | |||
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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ORAL ADMINISTRATION |
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Biological Half-life | PHARMACOKINETIC |
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