MACITENTAN

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

Structure Search

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)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204410s008lbl.pdf
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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Endothelin-1 receptor 6 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	Antagonist 2778		0.5 nM [IC50]
Endothelin B receptor 1 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	Antagonist 2778		391.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 35 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204410s008lbl.pdf	Primary		Approved 8429	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 2013

C_max

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

T_1/2

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 Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21541781	healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21541781	DLT: Headache, Nausea... Dose limiting toxicities: Headache (moderate, 5 patients) Nausea (2 patients) Vomiting (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/21541781
300 mg single, oral MTD Dose: 300 mg Route: oral Route: single Dose: 300 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/21541781	healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/21541781	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/21541781
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf	Other AEs: Fetal damage... Other AEs: Fetal damage Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf

AEs

AE	Significance	Dose	Population
Nausea	2 patients DLT	600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21541781	healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21541781
Vomiting	2 patients DLT	600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21541781	healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21541781
Headache	moderate, 5 patients DLT	600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21541781	healthy, 19– 49 years n = 6 Health Status: healthy Age Group: 19– 49 years Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21541781
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767 inducer 389 substrate 1037	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BSEP 402 NTCP 34 OATP1B1 788 OATP1B3 706 P-gp 1461 CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C19 1478 CYP2E1 882 CYP2C8 911 BCRP 699 MATE1 306 MATE2 263 OAT1 599 OAT3 642 OCT1 512 OCT3 150	P-gp 1537 CYP2C19 991 OATP1B1 406 OATP1B3 350 BCRP 561 BSEP 52 CYP2C8 693 MATE1 135 MATE2 96 NTCP 17 OAT1 326 OAT3 339 OCT1 327 OCT3 80	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63, 64	likely
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 55.0	no [IC50 14 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 55.0	no [IC50 6.9 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	no
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OCT3 150	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 54.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf 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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 55.0	unlikely [IC50 18 uM]
NTCP 35	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 55.0	unlikely [IC50 19 uM]
PXR 46	activator 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	yes [EC50 1.1 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	yes [IC50 21 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	yes [IC50 24 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 63.0	yes [IC50 5.6 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf 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% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 52, 61, 63, 65
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 51, 52, 61, 63, 64	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	minor
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	minor	no (co-administration study) Comment: warfarin had no significant impact on the exposure to macitentan Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
BSEP 52	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
MATE1 135	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
MATE2 96	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
NTCP 17	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
OCT3 80	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf Page: 10.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 7.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 52, 64	no	no (co-administration study) Comment: cyclosporine-A had no significant impact on the exposure to macitentan Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 52, 64
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 52, 64	no	no (co-administration study) Comment: cyclosporine-A had no significant impact on the exposure to macitentan Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Page: 52, 64

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf Page: 28.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:76607	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:76607
MolPort	MolPort-023-299-418	https://www.molport.com/shop/molecule-link/MolPort-023-299-418
Selleck Chemicals	macitentan	http://www.selleckchem.com/products/macitentan.html
ZINC	ZINC000043202140	http://zinc15.docking.org/substances/ZINC000043202140

PubMed

Title	Date	PubMed
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	22862294
Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension.	2015 Aug 15	26111581

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage is 10 mg once daily for oral administration.

Route of Administration: Oral

In Vitro Use Guide

Unknown

Name

Type

Language

MACITENTAN

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

Macitentan [WHO-DD]

Common Name

English

ACT 064992

Code

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