Back to discover

Protein / target

Endothelin-1 receptor

Encoded byEDNRAP25101Homo sapiensSwiss-Prot
UniProt: P25101Ensembl: ENSG00000151617HGNC: HGNC:3179NCBI Gene: 1909
Clinically validated
Therapeutic maturity
8
Approved medicines
Open Targets target-level
View by indication →
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

Phosphatidylinositol-4,5-bisphosphate phospholipase C

Strongest disease association

Coronary Artery Disease

Via encoding gene EDNRA · Genetic evidence · score 0.84

Therapeutic position

Established drug target

Small molecules

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Receptor for endothelin-1.

View complete UniProt function annotation

Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3

Subcellular location

Cell membrane
Domains and Gene Ontology detail (73)

Gene Ontology

  • Cplasma membrane
  • Fendothelin receptor activity
  • Fphosphatidylinositol-4,5-bisphosphate phospholipase C activity
  • Pactivation of adenylate cyclase activity
  • Paorta development
  • Partery smooth muscle contraction
  • Patrial cardiac muscle tissue development
  • Paxon extension
  • Paxonogenesis involved in innervation
  • Pblood vessel remodeling
  • Pbranching involved in blood vessel morphogenesis
  • Pcalcium ion transmembrane transport

427 aa · 49 kDa · 5 isoforms

Biological roles

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Ion channel gatingGOCell proliferation & survivalGOCell migrationGOCell-cycle regulationGOG protein-coupled signallingGOImmune signallingGO
View supporting evidence

Ion channel gating

  • ·calcium ion transmembrane transport
  • ·positive regulation of cation channel activity

Cell proliferation & survival

  • ·cell population proliferation

Cell migration

  • ·cardiac neural crest cell migration involved in outflow tract morphogenesis

Cell-cycle regulation

  • ·mitotic cell cycle

G protein-coupled signalling

  • ·G protein-coupled receptor signaling pathway
  • ·phospholipase C-activating G protein-coupled receptor signaling pathway

Immune signalling

  • ·cardiac neural crest cell migration involved in outflow tract morphogenesis
  • ·neural crest cell fate commitment

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Approved medicines with mapped indications

4 medicines · 4 areas

Approved therapies targeting this protein, grouped by what they are approved to treat — the disease-first view of the medicines below. Relationships come from the canonical approved-indication graph (ChEMBL phase-4), the same source as the drug cards.

Hypertension3 medicines
ambrisentanmacitentansitaxentan
Familial Primary Pulmonary Hypertension2 medicines
ambrisentanmacitentan
Hypertension, Pulmonary2 medicines
ambrisentanmacitentan
Glomerulonephritis, IGA1 medicine
sparsentan

8 medicines meet Open Targets' target-level approved-medicine definition; the 4 shown here are those on this page with a canonical approved disease indication in the graph. Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

4

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

sparsentan
Narrow target profileApprovedAntagonist

Endothelin receptor ET-A antagonist

Indicated for Glomerulonephritis, IGA

Direct interaction with this protein · 1 of 2 recorded protein targets — narrow recorded profile

sitaxentan
ApprovedAntagonist

Endothelin receptor, ET-A/ET-B antagonist

Indicated for Hypertension

Acts on a complex — shared with EDNRB · 1 of 2 recorded protein targets — narrow recorded profile

ambrisentan
ApprovedAntagonist

Endothelin receptor, ET-A/ET-B antagonist

Indicated for Familial Primary Pulmonary Hypertension, Hypertension, Hypertension, Pulmonary

Acts on a complex — shared with EDNRB · 1 of 2 recorded protein targets — narrow recorded profile

macitentan
ApprovedAntagonist

Endothelin receptor, ET-A/ET-B antagonist

Indicated for Familial Primary Pulmonary Hypertension, Hypertension, Hypertension, Pulmonary

Acts on a complex — shared with EDNRB · 1 of 2 recorded protein targets — narrow recorded profile

ChEMBL mechanism, action type, target identity and approved indications. Open Targets clinical status.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene EDNRA

Gene-level evidence surfaced through the gene EDNRAthat encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Hypertension
0.93Well supported

Genetic evidence dominant · Open Targets 0.68

Cardiovascular Diseases
0.89Well supported

Genetic evidence dominant · Open Targets 0.58

Coronary Artery Disease
0.86Well supported

Genetic evidence dominant · Open Targets 0.53

Heart Diseases
0.82Well supported

Genetic evidence dominant · Open Targets 0.51

Pulmonary arterial hypertension
0.76Well supported

Clinical evidence dominant · Open Targets 0.62

View evidence synthesis (5)
HypertensionWell supported
0.93
agreement 0.83–1.00
Genetic50%Clinical45%Literature6%

Open Targets aggregate 0.68 · 3 independent evidence families

Cardiovascular DiseasesWell supported
0.89
agreement 0.79–1.00
Genetic56%Clinical43%Literature1%

Open Targets aggregate 0.58 · 3 independent evidence families

Coronary Artery DiseaseWell supported
0.86
agreement 0.75–0.96
Genetic86%Clinical10%Literature5%

Open Targets aggregate 0.53 · 3 independent evidence families

Heart DiseasesWell supported
0.82
agreement 0.71–0.92
Genetic69%Clinical30%Literature0%

Open Targets aggregate 0.51 · 3 independent evidence families

Pulmonary arterial hypertensionWell supported
0.76
agreement 0.60–0.92
Clinical91%Literature9%

Open Targets aggregate 0.62 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations
Hypertension0.68
Pulmonary arterial hypertension0.62
Hypertension, Pulmonary0.59
Scleroderma, Systemic0.58
Cardiovascular Diseases0.58
Glomerulonephritis, IGA0.55
Coronary Artery Disease0.53
Prostatic Neoplasms0.52
Heart Diseases0.51

Drug development

16 compounds recorded · 8 approved · 8 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 4 drugs that target this protein in Forefront's canonical graph (4 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (10)
BQ-123Phase 2
DARUSENTANPhase 3
APROCITENTANApproval
MACITENTANApproval
SITAXENTANApproval
CLAZOSENTANApproval
SPARSENTANApproval
SITAXENTAN SODIUMApproval
ENRASENTANPhase 2
ZIBOTENTANPhase 3

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Strong

Approved Drug and Structure with Ligand support this modality.

Antibodies — Emerging

Feasibility evidence (go cc high conf and uniprot loc med conf) — no clinical-stage drug of this modality recorded.

Protein degraders — Emerging

Feasibility evidence (small molecule binder) — no clinical-stage drug of this modality recorded.

Other modalities — Strong

Advanced Clinical support this modality.

View underlying tractability evidence (9)
SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyAB · GO CC high confAB · UniProt loc med confAB · UniProt SigP or TMHMMPR · Small Molecule BinderOC · Advanced Clinical

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

bronchoconstrictionUrban et al. (2012)cleft palateLynch et al. (2017)vasoconstrictionUrban et al. (2012)glomerular and tubulointerstitial structural injuryLynch et al. (2017)teratogenicityUrban et al. (2012)increased cell proliferationLynch et al. (2017)receptor bindingToxCastincreased aldosterone secretionLynch et al. (2017)abnormal faceLynch et al. (2017)increased heart rateLynch et al. (2017)decreased urine excretionLynch et al. (2017)increased cardiac contractilityLynch et al. (2017)

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Clinical trials

30

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

A Multicenter, Open-label Single Arm Study to Evaluate the Safety and Efficacy of Sparsentan in Posttransplant Immunoglobulin A Nephropathy (IgAN) or Focal Segmental Glomerulosclerosis (FSGS) (SPARX)PHASE4

ACTIVE_NOT_RECRUITING · via sparsentan · NCT07219121

Comparison of Initial Dual Oral COMbination Therapy to MOnotherapy in Pulmonary Arterial Hypertension With Cardiovascular comorbiDITIESPHASE3

RECRUITING · via ambrisentan · NCT07245680

Effects of Combination Medical Therapy Followed by Balloon Pulmonary Angioplasty on Right Ventricular-PA Coupling and Hemodynamics in Chronic Thromboembolic Pulmonary HypertensionPHASE3

RECRUITING · via macitentan · NCT05140525

A Prospective, Open-label, Platform Study for Long-term Follow-up of Participants Using Study Intervention in Pulmonary Hypertension Parent StudiesPHASE3

RECRUITING · via macitentan · NCT05179876

View all trials (26)
A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients With Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period With Macitentan 75 mgPHASE3

ACTIVE_NOT_RECRUITING · via macitentan · NCT04273945

A Randomized, Multicenter, Double-blind, Parallel-group, Active-control Study of the Efficacy and Safety of Sparsentan for the Treatment of Immunoglobulin A NephropathyPHASE3

ACTIVE_NOT_RECRUITING · via sparsentan · NCT03762850

A Multi-Centre, Randomised, Open-Label, Phase II Study of Ambrisentan in Patients With Hepatorenal SyndromePHASE2

ACTIVE_NOT_RECRUITING · via ambrisentan · NCT06256432

Effects of Simultaneous ETA & AT1 Receptor Antagonism on Endothelial Function & Vascular Stiffness in ANCA-associated Vasculitis (SPARsentan in VASCulitis - SPARVASC)PHASE2

ACTIVE_NOT_RECRUITING · via sparsentan · NCT05630612

A Phase 2, Open-Label, Single-Arm, Cohort Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Sparsentan Treatment in Pediatric Subjects With Selected Proteinuric Glomerular DiseasesPHASE2

RECRUITING · via sparsentan · NCT05003986

A Multi-centre, Open-label, Exploratory Trial of the Safety and Activity of Sparsentan for the Treatment of Incident (Cohort A) and Recurrent (Cohort B) Patients With Immunoglobulin A NephropathyPHASE2

RECRUITING · via sparsentan · NCT04663204

Sparsentan for the Treatment of VEGF Signaling Pathway Inhibitor-Associated ProteinuriaPHASE1

NOT_YET_RECRUITING · via sparsentan · NCT07224776

Ambrisentan for the Treatment of Early-Stage Low-Risk Pulmonary Arterial Hypertension: A Multicenter, Randomized, Double-Blind, Placebo-Controlled ALEPH TrialNA

NOT_YET_RECRUITING · via ambrisentan · NCT06987097

A Multicenter, Randomized, Controlled, Double-blind, and Non-inferiority Clinical Trial to Compare the Efficacy of Sequential to Initial Combination Therapy in Patients With Pulmonary Arterial HypertensionNA

RECRUITING · via ambrisentan · NCT06968962

Impact of Endothelin-1 on the Development of Cardiac Allograft Vasculopathy in Heart Transplant Recipients: Endothelin Receptor Antagonism and Vasomotor FunctionPHASE4

COMPLETED · via macitentan · NCT05373108

Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction (CLAD) After Lung TransplantationPHASE4

WITHDRAWN · via macitentan · NCT02893176

A Safety and Clinical Efficacy Study Measuring Echocardiographic Composite Comparing Ambrisentan (Letairis®) After a Switch From Bosentan (Tracleer®) or Macintentan (Opsumit®) in Treatment of Pulmonary Arterial Hypertension (PAH)PHASE4

TERMINATED · via ambrisentan · NCT02885012

Prospective, Multicenter, Open-label Study Evaluating the Effects of First-line Oral Combination Therapy of Macitentan and Tadalafil in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (OPTIMA).PHASE4

TERMINATED · via macitentan · NCT02968901

A Randomized, Double-blind, Placebo-controlled, Prospective, Multicenter, Parallel Group Study to Assess the Safety and Efficacy of Macitentan in Patients With Portopulmonary HypertensionPHASE4

COMPLETED · via macitentan · NCT02382016

A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance ImagingPHASE4

COMPLETED · via macitentan · NCT02310672

The Effects of Ambrisentan on Exercise Capacity in Fontan PatientsPHASE4

COMPLETED · via ambrisentan · NCT01971580

Safely Change From Bosentan to Ambrisentan in Pulmonary HypertensionPHASE4

COMPLETED · via ambrisentan · NCT01330108

Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan: A Prospective Single Center, Open Label, Pilot StudyPHASE4

COMPLETED · via ambrisentan · NCT01051960

Safety and Efficacy Trial Using Ambrisentan for Pulmonary Hypertension Associated With Congestive Heart Failure With Preserved Left Ventricular Ejection FractionPHASE4

TERMINATED · via ambrisentan · NCT00840463

An Open-Label Uncontrolled Study of the Safety and Efficacy of Ambrisentan in Patients With Exercise Induced Pulmonary Arterial HypertensionPHASE4

COMPLETED · via ambrisentan · NCT01338636

An Open-label, Multicenter Study of Ambrisentan and a Phosphodiesterase Type-5 Inhibitor Combination Therapy in Subjects With Pulmonary Arterial Hypertension Who Have Demonstrated a Sub-Optimal Response to a Phosphodiesterase Type-5 InhibitorPHASE4

COMPLETED · via ambrisentan · NCT00617305

The Role of MACitentan on the Prevention of Residual Pulmonary vasculaR OcclusionPHASE3

WITHDRAWN · via macitentan · NCT05946811

A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients (>=3 Months to <15 Years) With Pulmonary Arterial HypertensionPHASE3

COMPLETED · via macitentan · NCT05167825

Initial Dual Oral coMbination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary hyperTensionPHASE2/PHASE3

COMPLETED · via macitentan · NCT04780932

A Prospective, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Adaptive Phase 3 Study With Open-label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary HypertensionPHASE3

TERMINATED · via macitentan · NCT04271475

mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms (TACTIC-E)PHASE2/PHASE3

COMPLETED · via ambrisentan · NCT04393246

ClinicalTrials.gov via the drug-target graph.

What's happening now

10

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for 4 drugs that target this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

  1. Regulatory approval2026-06-08

    Approval: MACITENTAN (ANDA211000)

    fda · regulatory · fda · via macitentan

  2. Regulatory approval2026-06-08

    Approval: MACITENTAN (ANDA211187)

    fda · regulatory · fda · via macitentan

  3. Regulatory approval2025-09-24

    Approval: Macitentan Accord (EMA)

    ema · regulatory · ema · via macitentan

  4. Regulatory approval2025-09-24

    Approval: Macitentan AccordPharma (EMA)

    ema · regulatory · ema · via macitentan

  5. Regulatory approval2024-04-19

    Approval: Filspari (EMA)

    ema · regulatory · ema · via sparsentan

  6. Regulatory approval2019-06-20

    Approval: Ambrisentan Viatris (previously Ambrisentan Mylan) (EMA)

    ema · regulatory · ema · via ambrisentan

  7. Safety communication2014-12-11

    Drug Safety Update: Sitaxentan (Thelin▼): worldwide withdrawal from the market

    mhra · safety · mhra · via sitaxentan

  8. Regulatory approval2013-12-20

    Approval: Opsumit (EMA)

    ema · regulatory · ema · via macitentan

  9. New publication2012-12-01
    Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study.

    Arthritis and rheumatism · 2012 · 49 citations · Europe PMC · via ambrisentan

  10. Regulatory approval2008-04-21

    Approval: Volibris (EMA)

    ema · regulatory · ema · via ambrisentan

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.