Aprocitentan

Summary

Aprocitentan (CHEMBL2165326) is an approved small-molecule antihypertensive agent (ATC C02KN01) targeting EDNRA and EDNRB; indicated across 4 conditions including hypertensive disorder and essential hypertension.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: C02KN01
• Targets: 2 (EDNRA, EDNRB)
• Indications: 4 conditions
• Clinical trials: 12
• Chemistry: 546.2 Da · C16H14Br2N6O4S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2165326
Name	Aprocitentan
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	25099191
ChEBI	CHEBI:76609
ATC	C02KN01
Molecular formula	C16H14Br2N6O4S
Molecular weight	546.2
InChIKey	DKULOVKANLVDEA-UHFFFAOYSA-N

SMILES: C1=CC(=CC=C1C2=C(N=CN=C2OCCOC3=NC=C(C=N3)Br)NS(=O)(=O)N)Br

IUPAC name: 5-(4-bromophenyl)-4-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-6-(sulfamoylamino)pyrimidine

ChEBI definition: A member of the class of sulfamides in which one of the amino groups of sulfonamide is substituted by a 5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl group. An active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension.

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

Other ChEBI roles (chemical / environmental): drug metabolite, xenobiotic metabolite.

Also known as: Act-132577, ACT-132577, Aprocitentan, Jeraygo, Macitentan metabolite m6, Tryvio, APROCITENTAN

Patent coverage: 54 distinct patent families (165 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 156 (95%) 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	6.7	0.1%	P25101
EDNRB	ETB receptor	Antagonist	5.5	0%	P24530

Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Endothelin receptor type B, Endothelin-1 receptor.

Bioactivity

ChEMBL activities: 4 potent at pChembl ≥ 5 of 4 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
EDNRA	8.47	IC50	3.4	nM	CHEMBL_ACT_12090997
EDNRA	8.47	IC50	3.4	nM	CHEMBL_ACT_19405746
EDNRB	6.01	IC50	987	nM	CHEMBL_ACT_12090996
EDNRB	6.01	IC50	987	nM	CHEMBL_ACT_19405783

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

4 indications (1 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
hypertensive disorder	4	MONDO:0005044	EFO:0000537
essential hypertension	2	MONDO:0001134	MONDO:0001134
liver disorder	1	MONDO:0005154	EFO:0001421
kidney disorder	1	MONDO:0005240	EFO:0003086

Clinical trials

Total trials: 12.

Phase distribution

Phase	Trials
PHASE1	9
PHASE3	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03541174	PHASE3	COMPLETED	A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety
NCT04162366	PHASE3	WITHDRAWN	A Research Study to Show Aprocitentan is Efficacious and Safe to Treat Patients With Uncontrolled Blood Pressure and Chronic Kidney Disease.
NCT02603809	PHASE2	COMPLETED	Dose-finding Study With ACT-132577 (Aprocitentan) in Participants With Essential Hypertension
NCT02708004	PHASE1	COMPLETED	Clinical Study to Assess Body Fluid Homeostasis After Administration of ACT-132577 in Healthy Subjects
NCT02841761	PHASE1	COMPLETED	A Study to Investigate the Effect of ACT-132577 on the Pharmacokinetics of Midazolam and 1-hydroxy Midazolam in Healthy Male Subjects
NCT03100591	PHASE1	COMPLETED	A Study to Evaluate ACT-132577 in Healthy Male Subjects
NCT03165071	PHASE1	COMPLETED	A Study to Evaluate ACT-132577 in Healthy Subjects and in People With Severe Kidney Disease
NCT03245229	PHASE1	COMPLETED	A Study in Healthy Male Subjects to Investigate Whether Administration of ACT-132577 Can Affect Rosuvastatin’s Fate in the Body (Amount and Time of Presence in the Blood)
NCT03586570	PHASE1	COMPLETED	A Study to Evaluate How Aprocitentan is Safe and How it is Absorbed and Broken Down in the Body of Japanese and Caucasian Subjects
NCT04252495	PHASE1	COMPLETED	The Effect of Hepatic Impairment on Aprocitentan Pharmacokinetics
NCT04281342	PHASE1	COMPLETED	To Study the Effect of Aprocitentan on the Electrical Activity of the Heart in Healthy Men and Women
NCT06799884	PHASE1	COMPLETED	A Drug-drug Interaction Trial in Healthy Female Participants to Investigate the Effect of Aprocitentan on Combined Hormonal Contraceptives

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

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
MACITENTAN	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