CONIVAPTAN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C32H26N4O2
Molecular Weight	498.5744
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=NC2=C(N1)C3=C(C=CC=C3)N(CC2)C(=O)C4=CC=C(NC(=O)C5=C(C=CC=C5)C6=CC=CC=C6)C=C4

InChI

InChIKey=IKENVDNFQMCRTR-UHFFFAOYSA-N

InChI=1S/C32H26N4O2/c1-21-33-28-19-20-36(29-14-8-7-13-27(29)30(28)34-21)32(38)23-15-17-24(18-16-23)35-31(37)26-12-6-5-11-25(26)22-9-3-2-4-10-22/h2-18H,19-20H2,1H3,(H,33,34)(H,35,37)

HIDE SMILES / InChI

Molecular Formula	C32H26N4O2
Molecular Weight	498.5744
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.drugs.com/ppa/conivaptan.html
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/21409494 | https://www.ncbi.nlm.nih.gov/pubmed/18926434

Conivaptan is an arginine vasopressin (AVP) receptor antagonist with affinity for AVP receptor subtypes V1A and V2. The antidiuretic action of AVP is mediated through activation of the V2 receptor, which functions to regulate water and electrolyte balance at the level of the collecting ducts in the kidney. Conivaptan was approved in 2004 for hyponatremia caused by syndrome of inappropriate antidiuretic hormone. Conicaptan is being evaluated for reduce intracranial pressure in patients with traumatic brain injury, and as a treatment for heart failure.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Vasopressin V1a receptor 17 Target ID: CHEMBL1889 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021697s003lbl.pdf	Antagonist 2778		0.43 nM [Ki]
Vasopressin V2 receptor 15 Target ID: CHEMBL1790 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021697s003lbl.pdf	Antagonist 2778		0.36 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Hyponatremia 4 Sources: https://www.drugs.com/ppa/conivaptan.html	Primary	Approved 8429	VAPRISOL IN 5% DEXTROSE IN PLASTIC CONTAINER Approved Use VAPRISOL is a vasopressin receptor antagonist indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia. Launch Date 1.13581438E12
Traumatic brain injury 9 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21409494	Palliative	Phase I 428	Unknown Approved Use Unknown
Liver cirrhosis 15 Sources: https://clinicaltrials.gov/ct2/show/NCT00592475	Palliative	Phase II 1132	Unknown Approved Use Unknown
Heart failure 103 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18926434	Palliative	Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
2681 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10638391	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
619 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021697s003lbl.pdf	40 mg/kg single, intravenous dose: 40 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
4813 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10638391	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.1 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10638391	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
5 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021697s003lbl.pdf	40 mg/kg single, intravenous dose: 40 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021697s003lbl.pdf	40 mg/kg single, intravenous dose: 40 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		CONIVAPTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
80 mg 1 times / day multiple, oral Highest studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16522696	unhealthy, 68.7 years (range: 35–90 years) n = 27 Health Status: unhealthy Condition: euvolemic hyponatremia \| hypervolemic hyponatremia Age Group: 68.7 years (range: 35–90 years) Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/16522696	Sources: https://pubmed.ncbi.nlm.nih.gov/16522696
120 mg 1 times / day multiple, intravenous Highest studied dose Dose: 120 mg, 1 times / day Route: intravenous Route: multiple Dose: 120 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021697lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: Congestive heart failure Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021697lbl.pdf	Other AEs: Hypotension, Thirst... Other AEs: Hypotension Thirst Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021697lbl.pdf
40 mg 1 times / day multiple, intravenous Recommended Dose: 40 mg, 1 times / day Route: intravenous Route: multiple Dose: 40 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_MEDR.pdf Page: p. 64	unhealthy, adult n = 445 Health Status: unhealthy Age Group: adult Population Size: 445 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_MEDR.pdf Page: p. 64	Disc. AE: Hypopituitarism, Infusion site reaction... AEs leading to discontinuation/dose reduction: Hypopituitarism (0.2%) Infusion site reaction (0.2%) Infusion site phlebitis (1.6%) Infusion related reaction (0.2%) Sepsis NOS (0.2%) Pneumonia NOS (0.2%) Blood creatinine increased (0.2%) Blood sodium increased (0.2%) Blood urea increased (0.2%) Heart rate increased (0.2%) Hypernatremia (0.8%) Epilepsy NOS (0.2%) Agitation (0.2%) Renal failure acute (0.2%) Respiratory arrest (0.2%) Respiratory failure (0.2%) Cyanosis peripheral (0.2%) Phlebitis NOS (0.2%) Phlebitis superficial (0.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_MEDR.pdf Page: p. 64
12.5 mg single, intravenous Dose: 12.5 mg Route: intravenous Route: single Dose: 12.5 mg Sources: https://clinicaltrials.gov/ct2/show/NCT00592475	unhealthy n = 6 Health Status: unhealthy Condition: Liver Cirrhosis Population Size: 6 Sources: https://clinicaltrials.gov/ct2/show/NCT00592475	Other AEs: Dizziness... Other AEs: Dizziness (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT00592475
20 mg 1 times / day multiple, intravenous Dose: 20 mg, 1 times / day Route: intravenous Route: multiple Dose: 20 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT00478192	unhealthy n = 20 Health Status: unhealthy Condition: Euvolemic or Hypervolemic Hyponatremia Population Size: 20 Sources: https://clinicaltrials.gov/ct2/show/NCT00478192	Other AEs: Coagulopathy, Cardiac failure congestive... Other AEs: Coagulopathy (serious, 1 patient) Cardiac failure congestive (serious, 2 patients) Multi-organ failure (serious, 1 patient) Hyponatraemia (serious, 1 patient) Transient ischaemic attack (serious, 1 patient) Renal failure (serious, 1 patient) Respiratory distress (serious, 1 patient) Hypocoagulable state (below serious, 1 patient) Leukocytosis (below serious, 1 patient) Arrhythmia ventricular (below serious, 1 patient) Abdominal discomfort (below serious, 1 patient) Abdominal distension (below serious, 2 patients) Abnormal bowel sounds (below serious, 1 patient) Constipation (below serious, 2 patients) Nausea (below serious, 2 patients) Fatigue (below serious, 1 patient) Hypothermia (below serious, 1 patient) Pain (below serious, 2 patients) Procedural pain (below serious, 1 patient) Breath sounds abnormal (below serious, 1 patient) Chest X-ray abnormal (below serious, 1 patient) Hypoalbuminaemia (below serious, 1 patient) Hypomagnesaemia (below serious, 2 patients) Hypophosphataemia (below serious, 1 patient) Hypovolaemia (below serious, 1 patient) Muscle spasms (below serious, 1 patient) Headache (below serious, 1 patient) Lethargy (below serious, 1 patient) Anxiety (below serious, 1 patient) Dysuria (below serious, 1 patient) Cough (below serious, 1 patient) Postnasal drip (below serious, 1 patient) Rales (below serious, 1 patient) Pruritus (below serious, 1 patient) Hypotension (below serious, 3 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT00478192
20 mg 2 times / day multiple, intravenous Dose: 20 mg, 2 times / day Route: intravenous Route: multiple Dose: 20 mg, 2 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT00478192	unhealthy n = 20 Health Status: unhealthy Condition: Euvolemic or Hypervolemic Hyponatremia Population Size: 20 Sources: https://clinicaltrials.gov/ct2/show/NCT00478192	Other AEs: Cardiac failure congestive, Pneumonia... Other AEs: Cardiac failure congestive (serious, 1 patient) Pneumonia (serious, 1 patient) Respiratory acidosis (serious, 1 patient) Coronary artery bypass (serious, 1 patient) Hypotension (serious, 1 patient) Dry eye (below serious, 1 patient) Constipation (below serious, 2 patients) Nausea (below serious, 1 patient) Vomiting (below serious, 2 patients) Chest pain (below serious, 1 patient) Fatigue (below serious, 1 patient) Oedema peripheral (below serious, 1 patient) Bronchitis chronic (below serious, 1 patient) Contusion (below serious, 1 patient) Blood pressure decreased (below serious, 1 patient) Cardiac murmur (below serious, 1 patient) Carotid bruit (below serious, 1 patient) Heart sounds abnormal (below serious, 1 patient) Dehydration (below serious, 1 patient) Hypernatraemia (below serious, 1 patient) Hypokalaemia (below serious, 1 patient) Neck pain (below serious, 1 patient) Headache (below serious, 1 patient) Insomnia (below serious, 2 patients) Psychotic disorder (below serious, 1 patient) Haematuria (below serious, 1 patient) Pruritus (below serious, 1 patient) Haematoma (below serious, 1 patient) Thrombophlebitis (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT00478192
22.5 mg single, intravenous Dose: 22.5 mg Route: intravenous Route: single Dose: 22.5 mg Sources: https://clinicaltrials.gov/ct2/show/NCT00592475	unhealthy n = 9 Health Status: unhealthy Condition: Liver Cirrhosis Population Size: 9 Sources: https://clinicaltrials.gov/ct2/show/NCT00592475	Other AEs: Atrial tachycardia, Urinary tract infection... Other AEs: Atrial tachycardia (serious, 1 patient) Urinary tract infection (serious, 1 patient) Encephalopathy hepatic (serious, 1 patient) Atrial flutter (below serious, 1 patient) Nausea (below serious, 1 patient) Vomiting (below serious, 1 patient) Polydipsia (below serious, 1 patient) Back pain (below serious, 1 patient) Productive cough (below serious, 1 patient) Dry skin (below serious, 1 patient) Phlebitis (below serious, 2 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT00592475
60 mg single, intravenous Dose: 60 mg Route: intravenous Route: single Dose: 60 mg Sources: https://clinicaltrials.gov/ct2/show/NCT00843986	unhealthy n = 6 Health Status: unhealthy Condition: Acute Decompensated Heart Failure Population Size: 6 Sources: https://clinicaltrials.gov/ct2/show/NCT00843986	Other AEs: Cardiac arrest, Atrial flutter... Other AEs: Cardiac arrest (serious, 1 patient) Atrial flutter (below serious, 1 patient) Ventricular tachycardia (below serious, 1 patient) Constipation (below serious, 1 patient) Infusion site erythema (below serious, 3 patients) Infusion site pain (below serious, 1 patient) Pyrexia (below serious, 1 patient) Heart rate increased (below serious, 1 patient) Muscle spasms (below serious, 1 patient) Pain in extremity (below serious, 1 patient) Headache (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT00843986

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A2 1524 CYP2C19 1478	P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 20, 48	strong [IC50 0.47 uM]	yes (co-administration study) Comment: coadministration with midazolam or simvastatin significantly increased both CYP3A4 substrates Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 20, 48
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 48.0	weak [IC50 198.3 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 48.0	yes [IC50 12.6 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021697s005lbl.pdf Page: 10, 48	yes [IC50 13.3 uM]	yes (co-administration study) Comment: coadministration with warfarin increased warfarin WUC by 14% amd Cmax by 17% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021697s005lbl.pdf Page: 10, 48
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 48.0	yes [IC50 19.2 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021697s005lbl.pdf Page: 10, 21	yes	yes (co-administration study) Comment: coadministration with digoxin resulted in increased Cmax by 79% and AUC by 43% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021697s005lbl.pdf Page: 10, 21

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 21, 48	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 38.0	yes		yes (co-administration study) Comment: ketoconazole increased conivaptan AUC 11-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_BIOPHARMR.pdf Page: 38.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_Vaprisol_PHARMR.pdf Page: 20, 25

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:681850	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:681850
ChemicalBook	CB51011161	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB51011161
MolPort	MolPort-046-703-477	https://www.molport.com/shop/molecule-link/MolPort-046-703-477
ZINC	ZINC000012503187	http://zinc15.docking.org/substances/ZINC000012503187

PubMed

Title	Date	PubMed
Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide.	2001 May	11343672
Body compartment volumes and composition after giving a vasopressin antagonist: changes are revealed by a tonicity balance.	2002 Feb	11812887
Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.	2002 Nov	12419640
Rationale for use of an exercise end point and design for the ADVANCE (A Dose evaluation of a Vasopressin ANtagonist in CHF patients undergoing Exercise) trial.	2003 Jan	12514672
Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis.	2003 Jul	12639215
Gateways to clinical trials.	2004 Jul-Aug	15349141
Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure.	2005 Jan 10	15659304
Gateways to clinical trials.	2005 Jan-Feb	15834459
Vasopressin antagonism: a future treatment option in heart failure.	2005 Mar	15695526
Conivaptan: a selective vasopressin antagonist for the treatment of heart failure.	2006 Jan	16375624
Hyponatremia and heart failure--treatment considerations.	2006 Jan-Feb	16470095
Vaptans and the treatment of water-retaining disorders.	2006 May	16713496
Molecule of the Month: Conivaptan hydrochloride.	2006 Nov	17220962
Diagnosis and management of hyponatremia in cancer patients.	2007 Dec	17701059
Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected].	2007 Fall	17919259
Recognition and treatment of hyponatremia in acutely ill hospitalized patients.	2007 Feb	17472815
A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).	2007 Jan	17202666
[Arginine vasopressin antagonism--new treatment option in chronic heart failure].	2007 Jan 18	17237865
Conivaptan: new treatment for hyponatremia.	2007 Jul 1	17592003
[Recent progress in vasopressin research on cardiovascular diseases].	2007 Jun	17657988
Intravenous conivaptan: effects on the QTc interval and other electrocardiographic parameters in healthy volunteers.	2007 Mar-Apr	17565921
Clinical practice. The syndrome of inappropriate antidiuresis.	2007 May 17	17507705
Current issues for nurse practitioners: Hyponatremia.	2007 Nov	17970857
Hyponatremia and vasopressin antagonism in congestive heart failure.	2007 Nov	17847041
Mechanisms, risks, and new treatment options for hyponatremia.	2008	18434717
Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia.	2008	18363040
Conivaptan: a step forward in the treatment of hyponatremia?	2008 Apr	18728836
[Etiology, diagnostics and therapy of hyponatremias].	2008 Jul 20	18617466
Hyponatremia: case vignettes.	2009 May	19523576

Patents

Sample Use Guides

In Vivo Use Guide

IV: 20 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 20 mg over 24 hours (0.83 mg/hour) for 2 to 4 days; may increase to a maximum dose of 40 mg over 24 hours (1.7 mg/hour) if serum sodium not rising sufficiently; total duration of therapy not to exceed 4 days. Note: If patient requires 40 mg/24 hours, may administer two consecutive 20 mg/100 mL premixed solutions over 24 hours (ie, 20 mg over 12 hours followed by 20 mg over 12 hours).

Route of Administration: Intravenous

In Vitro Use Guide

Binding of conivaptan with recombinant human vasopressin V1a and V2 receptors was studied using [3H]-Arg-vasopressin as a radioligand. Conivaptan binds to V1a with Ki of 0.43 and to V2 receptor with Ki of 0.36 nM.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:17:43 UTC 2023` Edited by `admin` on `Sat Dec 16 16:17:43 UTC 2023`
Record UNII	0NJ98Y462X
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CONIVAPTAN

Official Name

English

(1,1'-BIPHENYL)-2-CARBOXAMIDE, N-(4-((4,5-DIHYDRO-2-METHYLIMIDAZO(4,5-D)(1)BENZAZEPIN-6(1H)-YL)CARBONYL)PHENYL)-

Systematic Name

English

4''-((4,5-DIHYDRO-2-METHYLIMIDAZO(4,5-D)(1)BENZAZEPIN-6(1H)-YL)CARBONYL)-2-BIPHENYLCARBOXANILIDE

Common Name

English

CONIVAPTAN [VANDF]

Common Name

English

conivaptan [INN]

Common Name

English

CONIVAPTAN [MI]

Common Name

English

Conivaptan [WHO-DD]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000009945