Tolvaptan

Summary

Tolvaptan (CHEMBL344159) is an approved small molecule (ATC C03XA01) targeting AVPR1A and AVPR2; indicated across 13 conditions including heart failure and cardiovascular disorder.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: C03XA01
• Targets: 2 (AVPR1A, AVPR2)
• Indications: 13 conditions
• Clinical trials: 98
• Chemistry: 448.9 Da · C26H25ClN2O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL344159
Name	Tolvaptan
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	216237
ChEBI	CHEBI:231425
ATC	C03XA01
Molecular formula	C26H25ClN2O3
Molecular weight	448.9
InChIKey	GYHCTFXIZSNGJT-UHFFFAOYSA-N

SMILES: CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)O)C

IUPAC name: N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamide

ChEBI definition: A member of the class of benzazepines that is 2,3,4,5-tetrahydro-1H-1-benzazepine substituted by 2-methyl-4-(2-methylbenzamido)benzoyl, hydroxy, and chloro groups at positions 1, 5, and 7, respectively.

Also known as: Jinarc, Jynarque, OPC-41061, OPC-41061(TOLVAPTAN), Samsca, Tolvaptan, Tolvaptan accord, TOLVAPTAN, SID124894207, SID144206807, TOLVAPTAN (OPC-41061), TolvaptanÊ

Patent coverage: 1,029 distinct patent families (3,645 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 3,492 (96%) 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
AVPR1A	V1A receptor	Antagonist	7.9	4.6%	P37288
AVPR2	V2 receptor	Antagonist	9.37	0%	P30518

Broader ChEMBL bioactivity targets: 15 (assay-derived). Sample: Glucagon-like peptide 1 receptor, Vasopressin V2 receptor, Vasopressin V1a receptor, Thromboxane A2 receptor, Beta-2 adrenergic receptor, 5-hydroxytryptamine receptor 1A, Muscarinic acetylcholine receptor M1, 5-hydroxytryptamine receptor 2C, Histamine H1 receptor, Mu-type opioid receptor.

Bioactivity

ChEMBL activities: 23 potent at pChembl ≥ 5 of 26 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
AVPR2	9.37	Ki	0.43	nM	CHEMBL_ACT_70244
AVPR2	9	Ki	1	nM	CHEMBL_ACT_24397629
AVPR2	9	Ki	1	nM	CHEMBL_ACT_29072102
AVPR2	8.77	Ki	1.7	nM	CHEMBL_ACT_24911379
AVPR2	8.62	Ki	2.4	nM	CHEMBL_ACT_24853630
AVPR2	8.35	IC50	4.5	nM	CHEMBL_ACT_25751197
AVPR2	7.95	IC50	11.22	nM	CHEMBL_ACT_24911419
AVPR1A	7.5	Ki	32	nM	CHEMBL_ACT_24397601
AVPR1A	7.5	Ki	32	nM	CHEMBL_ACT_29072070
AVPR1A	6.53	Ki	296	nM	CHEMBL_ACT_24853655
OPRM1	6.39	Ki	410	nM	CHEMBL_ACT_25740871
AVPR1A	6.33	IC50	470	nM	CHEMBL_ACT_24397621
TMEM97	5.99	Ki	1031	nM	CHEMBL_ACT_25740872
ADRB2	5.47	EC50	3400	nM	CHEMBL_ACT_25751195
GPR119	5.4	EC50	4019	nM	CHEMBL_ACT_25751200
GLP1R	5.33	EC50	4644	nM	CHEMBL_ACT_25751199
HTR2C	5.31	Ki	4856	nM	CHEMBL_ACT_25740870
FFAR4	5.29	EC50	5108	nM	CHEMBL_ACT_25751198
OPRM1	5.17	AC50	6708	nM	CHEMBL_ACT_25158591
HRH1	5.17	Ki	6687	nM	CHEMBL_ACT_25740869
TBXA2R	5.13	AC50	7424	nM	CHEMBL_ACT_25198260
ABCB11	5.1	AC50	7869	nM	CHEMBL_ACT_25127163
ABCB11	5	IC50	9990	nM	CHEMBL_ACT_18129043

Target pathways

Aggregated over 2 target gene(s): AVPR1A, AVPR2.

Top Reactome pathways

8 total, by targets touching each:

Pathway	Targets	Genes
Vasopressin-like receptors	2	AVPR1A, AVPR2
G alpha (q) signalling events	1	AVPR1A
G alpha (s) signalling events	1	AVPR2
Vasopressin regulates renal water homeostasis via Aquaporins	1	AVPR2
Defective AVP does not bind AVPR1A,B and causes neurohypophyseal diabetes insipidus (NDI)	1	AVPR1A
Cargo recognition for clathrin-mediated endocytosis	1	AVPR2
Clathrin-mediated endocytosis	1	AVPR2
Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	AVPR2

Dominant GO biological processes

GO term	Targets
regulation of systemic arterial blood pressure by vasopressin	2
positive regulation of systemic arterial blood pressure	2
G protein-coupled receptor signaling pathway	2
positive regulation of cell population proliferation	2
telencephalon development	2
cellular response to hormone stimulus	2
positive regulation of vasoconstriction	2
signal transduction	2
positive regulation of blood pressure	2
maternal aggressive behavior	1
generation of precursor metabolites and energy	1
positive regulation of cytosolic calcium ion concentration	1
negative regulation of female receptivity	1
grooming behavior	1
blood circulation	1

Indications & clinical

Indications

13 indications (7 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
heart failure	4	MONDO:0005252	EFO:0003144
cardiovascular disorder	4	MONDO:0004995	EFO:0000319
congestive heart failure	4	MONDO:0005009	EFO:0000373
inappropriate ADH syndrome	4	MONDO:0006802	EFO:1000982
autosomal dominant polycystic kidney disease	4	MONDO:0004691	EFO:1001496
polycystic kidney disease	4	MONDO:0020642	EFO:0008620
cirrhosis of liver	3	MONDO:0005155	EFO:0001422
carcinoma	2	MONDO:0004993	EFO:0000313
kidney disorder	2	MONDO:0005240	EFO:0003086
chronic kidney disease	2	MONDO:0005300	MONDO:0024327

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

Clinical trials

Total trials: 98.

Phase distribution

Phase	Trials
PHASE3	34
PHASE2	20
PHASE4	19
Not specified	14
PHASE1	8
PHASE2/PHASE3	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01199198	PHASE4	COMPLETED	Tolvaptan in Hyponatremic Cancer Patients
NCT01292304	PHASE4	COMPLETED	Tolvaptan for Ascites in Cirrhotic Patients
NCT01346072	PHASE4	COMPLETED	Pilot Study of Using Copeptin to Predict Response to Tolvaptan
NCT01439009	PHASE4	COMPLETED	Effect of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients
NCT01552590	PHASE4	TERMINATED	Effect of Samsca on Control of Hyponatremia and Extracellular Fluid in Cirrhotic Patients With Ascites
NCT01663662	PHASE4	WITHDRAWN	The Use of Tolvaptan to Prevent Renal Dysfunction in High Risk Patients With Heart Failure-Pilot Study
NCT01716611	PHASE4	UNKNOWN	Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites
NCT01863511	PHASE4	COMPLETED	Tolvaptan/Ultrafiltration in the Treatment of Acute Heart Failure
NCT01890694	PHASE4	TERMINATED	Tolvaptan to Reduce Length of Stay in Hospitalized Patients With Cirrhosis and Hyponatremia
NCT01973140	PHASE4	COMPLETED	Effects of Tolvaptan in Healthy Adults
NCT02183792	PHASE4	COMPLETED	Aquaresis Utility for Hyponatremic Acute Heart Failure Study
NCT02352285	PHASE4	TERMINATED	Outcome and Treatment Quality Study of Tolvaptan to Treat Hyponatremia in Patients With Heart Failure
NCT02476409	PHASE4	COMPLETED	Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders
NCT02606253	PHASE4	COMPLETED	Comparison of Oral or Intravenous Thiazides vs Tolvaptan in Diuretic Resistant Decompensated Heart Failure
NCT02644616	PHASE4	COMPLETED	The Safety and Efficacy of Tolvaptan for Patients With Tricuspid Regurgitation and Right Heart Failure After Left Heart Valves Replacement
NCT02666651	PHASE4	UNKNOWN	Regional Tolvaptan Registry
NCT02959411	PHASE4	TERMINATED	Tolvaptan for Advanced or Refractory Heart Failure
NCT03596957	PHASE4	UNKNOWN	Subacute Effect of Tolvaptan on Total Kidney Volume in Adult Patients With Autosomal Dominant Polycystic Kidney Disease
NCT03949894	PHASE4	COMPLETED	Evaluating the Safety and effectivenesS in Adult KorEaN Patients Treated With Tolvaptan for Management of Autosomal domInAnt poLycystic Kidney Disease
NCT04782258	PHASE3	RECRUITING	A Study to See Iftolvaptan is Safe in Infants and Children Who at Enrollment Are 28 Days to Less Than 18 Years Old withAutosomal Recessive Polycystic Kidney Disease (ARPKD)
NCT00071331	PHASE3	COMPLETED	EVEREST: Efficacy of Vasopressin Antagonism in hEart failuRE: Outcome Study With Tolvaptan
NCT00072683	PHASE3	COMPLETED	SALT Trial Study of Ascending Levels of Tolvaptan in Hyponatremia
NCT00201994	PHASE3	COMPLETED	SALT-2 Trial Study of Ascending Levels of Tolvaptan in Hyponatremia
NCT00428948	PHASE3	COMPLETED	Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT00462670	PHASE3	COMPLETED	A Double-blind, Placebo-controlled Study of OPC-41061 in the Treatment of Cardiac Edema (Congestive Heart Failure)
NCT00525265	PHASE3	COMPLETED	A Clinical Pharmacological Study of OPC-41061 in the Treatment of Cardiac Edema (Congestive Heart Failure)
NCT00544869	PHASE3	COMPLETED	A Study of OPC-41061 in Subjects With Cardiac-induced Edema (Congestive Heart Failure)
NCT00550459	PHASE3	COMPLETED	Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (QD) on Cognitive and Neurological Function in Elderly Hyponatremic Patients
NCT01022424	PHASE3	COMPLETED	A Long-term Administration Study of OPC-41061 in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) (2) [Extension of Study 156-05-002]
NCT01048788	PHASE3	COMPLETED	A Trial of OPC-41061 in Patients With Hepatic Edema - Investigation of the Safety of Treatment at 7.5 mg Beyond 7 Days and of the Effect of Dose Escalation to 15 mg
NCT01050530	PHASE3	COMPLETED	A Trial to Investigate the Efficacy of OPC-41061 Administered at a Dose of 7.5 mg in Patients With Hepatic Edema
NCT01114828	PHASE3	COMPLETED	A Study to Investigate Pharmacodynamics and Pharmacokinetics of OPC-41061 in Patients With Hepatic Edema
NCT01214421	PHASE3	COMPLETED	Tolvaptan Extension Study in Participants With ADPKD
NCT01227512	PHASE3	TERMINATED	Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia
NCT01280721	PHASE3	COMPLETED	A Study to Investigate the Long-term Safety and Efficacy of Tolvaptan in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) [Extension of Trial 156-04-251 in Japan]
NCT01349348	PHASE3	COMPLETED	Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites
NCT01507727	PHASE2/PHASE3	UNKNOWN	Efficacy and Safety Study of the Tolvaptan Tablets in Patients With Non-hypovolemic Non-acute Hyponatremia
NCT01556646	PHASE3	COMPLETED	Effect of Tolvaptan on Cognitive Function in Cirrhosis
NCT01618448	PHASE3	COMPLETED	Efficacy and Safety of Tolvaptan in the Treatment of Cardiac-Induced Edema in Patients With Heart Failure
NCT01644331	PHASE3	COMPLETED	Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure

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.

143 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
PIMOZIDE	ChEMBL + PubChem	Phase 4 (approved)	AVPR1A, AVPR2
RIFAMPIN	ChEMBL + PubChem	Phase 4 (approved)	AVPR1A, AVPR2
TEGASEROD	ChEMBL + PubChem	Phase 4 (approved)	AVPR1A, AVPR2
ATOSIBAN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
BALSALAZIDE	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
BOSUTINIB	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
CARBETOCIN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
CHLORHEXIDINE	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
CONIVAPTAN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
DESMOPRESSIN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
FLUSPIRILENE	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
MOZAVAPTAN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
NITAZOXANIDE	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
OXYTOCIN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
PYRVINIUM	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
RIFAXIMIN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
VASOPRESSIN	ChEMBL	Phase 4 (approved)	AVPR1A, AVPR2
BALOVAPTAN	ChEMBL	Phase 3	AVPR1A, AVPR2
LIXIVAPTAN	ChEMBL	Phase 3	AVPR1A, AVPR2
OTILONIUM BROMIDE	ChEMBL	Phase 3	AVPR1A, AVPR2
BENZETHONIUM	ChEMBL	Phase 2	AVPR1A, AVPR2
DOMIPHEN	ChEMBL	Phase 2	AVPR1A, AVPR2
NELIVAPTAN	ChEMBL	Phase 2	AVPR1A, AVPR2
ORNIPRESSIN	ChEMBL	Phase 2	AVPR1A, AVPR2
PECAVAPTAN	ChEMBL	Phase 2	AVPR1A, AVPR2
RELCOVAPTAN	ChEMBL	Phase 2	AVPR1A, AVPR2
SELEPRESSIN	ChEMBL	Phase 2	AVPR1A, AVPR2
Abiraterone	PubChem	Approved	AVPR1A, AVPR2
acetylcysteine	PubChem	Approved	AVPR1A, AVPR2
Aclidinium Bromide	PubChem	Approved	AVPR1A, AVPR2
Acyclovir	PubChem	Approved	AVPR1A, AVPR2
Afatinib	PubChem	Approved	AVPR1A, AVPR2
Allopurinol	PubChem	Approved	AVPR1A, AVPR2
Almotriptan	PubChem	Approved	AVPR1A, AVPR2
Alogliptin	PubChem	Approved	AVPR1A, AVPR2
aminolevulinic acid	PubChem	Approved	AVPR1A, AVPR2
Anagrelide	PubChem	Approved	AVPR1A, AVPR2
Apixaban	PubChem	Approved	AVPR1A, AVPR2
Aprepitant	PubChem	Approved	AVPR1A, AVPR2
Belzutifan	PubChem	Approved	AVPR1A, AVPR2
Bosentan	PubChem	Approved	AVPR1A, AVPR2
Clofarabine	PubChem	Approved	AVPR1A, AVPR2
Clozapine	PubChem	Approved	AVPR1A, AVPR2
Crizotinib	PubChem	Approved	AVPR1A, AVPR2
Dacarbazine	PubChem	Approved	AVPR1A, AVPR2
Desloratadine	PubChem	Approved	AVPR1A, AVPR2
Desoxycorticosterone Pivalate	PubChem	Approved	AVPR1A, AVPR2
Didanosine	PubChem	Approved	AVPR1A, AVPR2
Dihydroergotamine	PubChem	Approved	AVPR1A, AVPR2
Erythromycin	PubChem	Approved	AVPR1A, AVPR2
Ethambutol	PubChem	Approved	AVPR1A, AVPR2
Fidaxomicin	PubChem	Approved	AVPR1A, AVPR2
Fulvestrant	PubChem	Approved	AVPR1A, AVPR2
Ganciclovir	PubChem	Approved	AVPR1A, AVPR2
Gefitinib	PubChem	Approved	AVPR1A, AVPR2
Glycopyrrolate	PubChem	Approved	AVPR1A, AVPR2
Leucovorin	PubChem	Approved	AVPR1A, AVPR2
Linagliptin	PubChem	Approved	AVPR1A, AVPR2
Methotrexate	PubChem	Approved	AVPR1A, AVPR2
Olanzapine	PubChem	Approved	AVPR1A, AVPR2