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Identification
Name Conivaptan
Accession Number DB00872 (APRD01302)
Type small molecule
Groups approved
Description

Conivaptan is a non-peptide inhibitor of antidiuretic hormone (vasopressin). It was approved in 2004 for hyponatremia (low blood sodium levels) caused by syndrome of inappropriate antidiuretic hormone (SIADH). Conivaptan inhibits both isotypes of the vasopressin receptor (V1a and V2).
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • conivaptan
  • Conivaptan hydrochloride
  • YM 087
  • YM-087
Brand names
  • Vaprisol
Brand name mixtures Not Available
Categories
  • Aquaresis promoters
CAS number 210101-16-9
Weight Average: 498.5744
Monoisotopic: 498.205576096
Chemical Formula C32H26N4O2
InChI Key InChIKey=IKENVDNFQMCRTR-UHFFFAOYSA-N
InChI
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)
Plain Text
IUPAC Name
N-[4-({4-methyl-3,5,9-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),2(6),3,11,13-pentaen-9-yl}carbonyl)phenyl]-2-phenylbenzamide
SMILES
CC1=NC2=C(CCN(C(=O)C3=CC=C(NC(=O)C4=C(C=CC=C4)C4=CC=CC=C4)C=C3)C3=C2C=CC=C3)N1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Statins
Substructures
  • Statins
  • Amino Ketones
  • Phenylpropenes
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Biphenyl and Derivatives
  • Carboxylic Acids and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Cinnamaldehydes
  • Carboxamides and Derivatives
  • Imines
  • Benzoyl Derivatives
  • Cyanamides
  • Benzamides
  • Anilines
Pharmacology
Indication For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients.
Pharmacodynamics Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V1A and V2 receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular 1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality.
Mechanism of action Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V1A and V2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water.
Absorption Not Available
Volume of distribution Not Available
Protein binding 99%
Metabolism

CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V1a and V2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively.
Route of elimination Not Available
Half life 5 hours
Clearance Not Available
Toxicity Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Astellas pharma us inc
Packagers
Dosage forms Not Available
Prices
Unit description Cost Unit
Vaprisol 20 mg/100 ml bag 6.3 USD ml
Patents
Country Patent Number Approved Expires
United States 5723606 1999-12-15 2019-12-15
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Very slightly soluble (0.15 mg/mL at 23oC) PhysProp
logP 6.3 PhysProp
Predicted Properties
Property Value Source
water solubility 1.75e-03 g/l ALOGPS
logP 5.23 ALOGPS
logP 5.44 ChemAxon Molconvert
logS -5.46 ALOGPS
pKa 13.54 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 78.09 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 150.83 ChemAxon Molconvert
polarizability 55.51 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. Pubmed
  2. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. Pubmed
  3. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. Pubmed
External Links
Resource Link
KEGG Drug D01236 Link_out
PubChem Compound 151171 Link_out
PubChem Substance 46504533 Link_out
ChemSpider 133239 Link_out
ChEBI 681850 Link_out
ChEMBL 681850 Link_out
Therapeutic Targets Database DNC001525 Link_out
Drug Product Database 0 Link_out
Drugs.com http://www.drugs.com/cdi/conivaptan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Conivaptan Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (145.4 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Vasopressin V1a receptor

Pharmacological action: yes
Actions: antagonist

Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl- inositol-calcium second messenger system. Has been involved in social behaviors, including affiliation and attachment

Organism class: human
UniProt ID: P37288 Link_out
Gene: AVPR1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. Pubmed
  3. Wada K, Matsukawa U, Fujimori A, Arai Y, Sudoh K, Sasamata M, Miyata K: A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Biol Pharm Bull. 2007 Jan;30(1):91-5. Pubmed
  4. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. Pubmed
  5. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. Pubmed
  6. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N: Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006 Jun;91(6):2145-52. Epub 2006 Mar 7. Pubmed
  7. Annane D, Decaux G, Smith N: Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med Sci. 2009 Jan;337(1):28-36. Pubmed
  8. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. Pubmed
  9. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. Pubmed
  10. Hoque MZ, Arumugham P, Huda N, Verma N, Afiniwala M, Karia DH: Conivaptan: promise of treatment in heart failure. Expert Opin Pharmacother. 2009 Sep;10(13):2161-9. Pubmed

2. Vasopressin V2 receptor

Pharmacological action: yes
Actions: antagonist

Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase

Organism class: human
UniProt ID: P30518 Link_out
Gene: AVPR2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Wada K, Fujimori A, Matsukawa U, Arai Y, Sudoh K, Yatsu T, Sasamata M, Miyata K: Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure. Eur J Pharmacol. 2005 Jan 10;507(1-3):145-51. Epub 2005 Jan 1. Pubmed
  3. Palm C, Pistrosch F, Herbrig K, Gross P: Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med. 2006 Jul;119(7 Suppl 1):S87-92. Pubmed
  4. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. Pubmed
  5. Wada K, Matsukawa U, Fujimori A, Arai Y, Sudoh K, Sasamata M, Miyata K: A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Biol Pharm Bull. 2007 Jan;30(1):91-5. Pubmed
  6. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. Pubmed
  7. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. Pubmed
  8. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N: Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006 Jun;91(6):2145-52. Epub 2006 Mar 7. Pubmed
  9. Annane D, Decaux G, Smith N: Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med Sci. 2009 Jan;337(1):28-36. Pubmed
  10. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. Pubmed
  11. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. Pubmed
  12. Hoque MZ, Arumugham P, Huda N, Verma N, Afiniwala M, Karia DH: Conivaptan: promise of treatment in heart failure. Expert Opin Pharmacother. 2009 Sep;10(13):2161-9. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.