Macitentan

Summary

Macitentan (CHEMBL2103873) is an approved small-molecule endothelin receptor antagonist (ATC C02KX04) targeting EDNRA and EDNRB; indicated across 11 conditions including pulmonary arterial hypertension and hypertensive disorder.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: C02KX04
• Targets: 2 (EDNRA, EDNRB)
• Indications: 11 conditions
• Clinical trials: 53
• Chemistry: 588.3 Da · C19H20Br2N6O4S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2103873
Name	Macitentan
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	16004692
ChEBI	CHEBI:76607
ATC	C02KX04
Molecular formula	C19H20Br2N6O4S
Molecular weight	588.3
InChIKey	JGCMEBMXRHSZKX-UHFFFAOYSA-N

SMILES: CCCNS(=O)(=O)NC1=C(C(=NC=N1)OCCOC2=NC=C(C=N2)Br)C3=CC=C(C=C3)Br

IUPAC name: 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine

ChEBI definition: A member of the class of sulfamides in which the two amino groups of sulfonamide are substituted by 5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl and propyl groups. An orphan drug used for the treatment of pulmonary arterial hypertension.

Pharmacological roles (ChEBI): endothelin receptor antagonist, antihypertensive agent, orphan drug.

Also known as: ACT 064992, ACT-064992, Macitentan, Macitentan component of opsynvi, Opsumit, MACITENTAN, SID174007274

Patent coverage: 567 distinct patent families (1,372 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,292 (94%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
EDNRA	ETA receptor	Antagonist	9.3	0.1%	P25101
EDNRB	ETB receptor	Antagonist	6.41	0%	P24530

Broader ChEMBL bioactivity targets: 5 (assay-derived). Sample: Endothelin receptor type B, Sodium-dependent noradrenaline transporter, D(3) dopamine receptor, Endothelin-1 receptor, Translocator protein.

Bioactivity

ChEMBL activities: 9 potent at pChembl ≥ 5 of 9 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
EDNRA	9.3	IC50	0.5	nM	CHEMBL_ACT_12091110
EDNRA	9.3	IC50	0.5	nM	CHEMBL_ACT_19405719
EDNRA	8.47	IC50	3.4	nM	CHEMBL_ACT_19405790
EDNRB	6.41	IC50	391	nM	CHEMBL_ACT_12091054
EDNRB	6.41	IC50	391	nM	CHEMBL_ACT_19405756
EDNRB	6.01	IC50	987	nM	CHEMBL_ACT_19405791
DRD3	6	Ki	1004	nM	CHEMBL_ACT_25741380
TSPO	5.67	Ki	2118	nM	CHEMBL_ACT_25741383
SLC6A2	5.32	Ki	4831	nM	CHEMBL_ACT_25741381

Target pathways

Aggregated over 2 target gene(s): EDNRA, EDNRB.

Top Reactome pathways

3 total, by targets touching each:

Pathway	Targets	Genes
Peptide ligand-binding receptors	2	EDNRA, EDNRB
G alpha (q) signalling events	2	EDNRA, EDNRB
Transcriptional and post-translational regulation of MITF-M expression and activity	1	EDNRB

Dominant GO biological processes

GO term	Targets
regulation of heart rate	2
signal transduction	2
G protein-coupled receptor signaling pathway	2
phospholipase C-activating G protein-coupled receptor signaling pathway	2
positive regulation of cytosolic calcium ion concentration	2
regulation of blood pressure	2
gene expression	2
heparin proteoglycan metabolic process	2
vasoconstriction	2
positive regulation of canonical NF-kappaB signal transduction	2
developmental pigmentation	2
enteric nervous system development	2
sodium ion homeostasis	2
canonical Wnt signaling pathway	2
establishment of endothelial barrier	2

Indications & clinical

Indications

11 indications (4 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
pulmonary arterial hypertension	4	MONDO:0015924	EFO:0001361
hypertensive disorder	4	MONDO:0005044	EFO:0000537
pulmonary hypertension	4	MONDO:0005149	MONDO:0005149
systemic sclerosis	3	MONDO:0005100	EFO:0000717
congenital heart disease	3	MONDO:0005453	EFO:0005207
ulcer disease	3	MONDO:0043839	MONDO:0043839
pulmonary embolism	3	MONDO:0005279	EFO:0003827
idiopathic pulmonary fibrosis	2	MONDO:0800504	EFO:0000768
heart failure	2	MONDO:0005252	EFO:0003144
glioblastoma	1	MONDO:0018177	EFO:0000519

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 53.

Phase distribution

Phase	Trials
PHASE3	22
PHASE1	14
PHASE2	10
PHASE4	5
PHASE2/PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02382016	PHASE4	COMPLETED	PORtopulmonary Hypertension Treatment wIth maCitentan - a randOmized Clinical Trial
NCT02893176	PHASE4	WITHDRAWN	Macitentan in the Treatment of Organ Rejection After Lung Transplantation
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT05373108	PHASE4	COMPLETED	Endothelin-1 and Cardiac Allograft Vasculopathy (CAV)
NCT04273945	PHASE3	ACTIVE_NOT_RECRUITING	Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension
NCT05140525	PHASE3	RECRUITING	Effects of Combination Medical Therapy Followed by BPA on Right Ventricular-PA Coupling and Hemodynamics in CTEPH
NCT05179876	PHASE3	RECRUITING	A Study Providing Treatment Access in Participants With Pulmonary Hypertension Completing a Parent Study and Having no Other Option
NCT00660179	PHASE3	COMPLETED	Study of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension
NCT00667823	PHASE3	COMPLETED	Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension
NCT01474109	PHASE3	COMPLETED	Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
NCT01474122	PHASE3	TERMINATED	Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
NCT01743001	PHASE3	COMPLETED	Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome
NCT01841762	PHASE3	COMPLETED	Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument
NCT01847014	PHASE3	TERMINATED	Clinical Study of Macitentan in Patients With PAH to Psychometrically Validate PAH-SYMPACT Instrument
NCT02081690	PHASE3	TERMINATED	A Pulmonary Arterial Hypertension Study With Macitentan to Validate the PAH-SYMPACT™ in France, Italy and Spain
NCT02112487	PHASE3	COMPLETED	Extension of the Psychometric Validation Study ORCHESTRA in Patients With PAH
NCT02558231	PHASE3	COMPLETED	The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
NCT02932410	PHASE3	COMPLETED	A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03422328	PHASE3	COMPLETED	A Clinical Study to Investigate the Long-term Safety of the Drug Macitentan in Patients With Pulmonary Hypertension Who Were Previously Treated With Macitentan in Clinical Studies.
NCT03775421	PHASE3	TERMINATED	An Upcoming Clinical Study to Measure the Safety and Impact of a Drug Called Macitentan in Teenage and Adult Fontan Patients.
NCT03809650	PHASE3	TERMINATED	A Clinical Study to Find Out if Macitentan is Effective and Safe in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH).
NCT03904693	PHASE3	COMPLETED	Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
NCT04271475	PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension
NCT04780932	PHASE2/PHASE3	COMPLETED	Initial Dual Oral Combination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension
NCT05167825	PHASE3	COMPLETED	A Study of Macitentan in Japanese Pediatric Participants With Pulmonary Arterial Hypertension
NCT05946811	PHASE3	WITHDRAWN	Macitentan to Prevent PRVO
NCT00903331	PHASE2	COMPLETED	Macitentan Use in an Idiopathic Pulmonary Fibrosis Clinical Study
NCT01346930	PHASE2	WITHDRAWN	Safety and Tolerability Study of Macitentan in Patients With Idiopathic Pulmonary Fibrosis
NCT02021292	PHASE2	COMPLETED	Clinical Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension
NCT02060721	PHASE2	COMPLETED	Clinical Study to Assess the Safety, Tolerability and Efficacy of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension
NCT02070991	PHASE2	COMPLETED	Clinical Study to Evaluate the Safety and Tolerability of Macitentan in Subjects With Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH) Due to Left Ventricular Dysfunction
NCT02554903	PHASE2	COMPLETED	Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation
NCT02651272	PHASE2	TERMINATED	Macitentan in Pulmonary Hypertension of Sickle Cell Disease
NCT03153111	PHASE2	COMPLETED	A Study to Evaluate Whether Macitentan is an Effective and Safe Treatment for Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease
NCT03362047	PHASE2	COMPLETED	(RIGHT HEART III Study - Right Ventricular Hemodynamic Evaluation and Response to Treatment)
NCT03714815	PHASE2	TERMINATED	A Long Term Study to Find Out if Macitentan is an Effective and Safe Treatment for Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease
NCT02050802	PHASE1	COMPLETED	Study to Assess the Effect of Macitentan on the Electrocardiogram (ECG) in Healthy Male and Female Subjects
NCT03215966	PHASE1	COMPLETED	A Study to Compare the Macitentan-tadalafil Fixed Dose Combination Tablet Relative to the Concomitant Administration of the Reference Tablets of Macitentan and Tadalafil in Healthy Subjects

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 5 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

50 molecules share ≥1 primary target. Top 50 by shared-target count:

Molecule	Source	Status	Shared targets
BOSENTAN	ChEMBL + PubChem	Phase 4 (approved)	EDNRA, EDNRB
AMBRISENTAN	ChEMBL	Phase 4 (approved)	EDNRA, EDNRB
APROCITENTAN	ChEMBL	Phase 4 (approved)	EDNRA, EDNRB
SITAXENTAN	ChEMBL	Phase 4 (approved)	EDNRA, EDNRB
SULFISOXAZOLE	ChEMBL	Phase 4 (approved)	EDNRA, EDNRB
ATRASENTAN	ChEMBL	Phase 3	EDNRA, EDNRB
AVOSENTAN	ChEMBL	Phase 3	EDNRA, EDNRB
CLAZOSENTAN	ChEMBL	Phase 3	EDNRA, EDNRB
DARUSENTAN	ChEMBL	Phase 3	EDNRA, EDNRB
TEZOSENTAN	ChEMBL	Phase 3	EDNRA, EDNRB
ENDOTHELIN	ChEMBL	Phase 2	EDNRA, EDNRB
ENRASENTAN	ChEMBL	Phase 2	EDNRA, EDNRB
FELOPRENTAN	ChEMBL	Phase 2	EDNRA, EDNRB
Dihydroergotamine	PubChem	Approved	EDNRA, EDNRB
Fidaxomicin	PubChem	Approved	EDNRA, EDNRB
Propoxyphene	PubChem	Approved	EDNRA, EDNRB
Pyrazinamide	PubChem	Approved	EDNRA, EDNRB
SPARSENTAN	ChEMBL + PubChem	Phase 4 (approved)	EDNRA
ACYCLOVIR	ChEMBL	Phase 4 (approved)	EDNRA
AMIODARONE	ChEMBL	Phase 4 (approved)	EDNRA
ENOXACIN	ChEMBL	Phase 4 (approved)	EDNRA
FLUOXETINE	ChEMBL	Phase 4 (approved)	EDNRA
GRAMICIDIN	ChEMBL	Phase 4 (approved)	EDNRA
IRBESARTAN	ChEMBL	Phase 4 (approved)	EDNRA
MAZINDOL	ChEMBL	Phase 4 (approved)	EDNRB
MELOXICAM	ChEMBL	Phase 4 (approved)	EDNRA
MODAFINIL	ChEMBL	Phase 4 (approved)	EDNRB
NITAZOXANIDE	ChEMBL	Phase 4 (approved)	EDNRA
PIOGLITAZONE	ChEMBL	Phase 4 (approved)	EDNRA
SULFATHIAZOLE	ChEMBL	Phase 4 (approved)	EDNRA
SUNITINIB	ChEMBL	Phase 4 (approved)	EDNRA
EXISULIND	ChEMBL	Phase 3	EDNRA
ZIBOTENTAN	ChEMBL	Phase 3	EDNRA
BQ-123	ChEMBL	Phase 2	EDNRA
EDONENTAN	ChEMBL	Phase 2	EDNRA
FANDOSENTAN	ChEMBL	Phase 2	EDNRA
Aclidinium Bromide	PubChem	Approved	EDNRB
Afatinib	PubChem	Approved	EDNRA
Alogliptin	PubChem	Approved	EDNRB
Apixaban	PubChem	Approved	EDNRA
Belzutifan	PubChem	Approved	EDNRB
Binimetinib	PubChem	Approved	EDNRA
chenodiol	PubChem	Approved	EDNRA
Desloratadine	PubChem	Approved	EDNRB
Fulvestrant	PubChem	Approved	EDNRA
Imipenem	PubChem	Approved	EDNRA
Methotrexate	PubChem	Approved	EDNRB
Olmesartan Medoxomil	PubChem	Approved	EDNRB
Tafamidis	PubChem	Approved	EDNRA
Tiotropium Bromide Monohydrate	PubChem	Approved	EDNRB