Identification

Name
Terlipressin
Accession Number
DB02638  (EXPT03310)
Type
Small Molecule
Groups
Approved, Investigational
Description

Terlipressin is an analogue of vasopressin used as a vasoactive drug in the management of hypotension. It has been found to be effective when norepinephrine does not help. [Wikipedia]

Structure
Thumb
Synonyms
  • Terlipressin
  • Terlipressina
  • Terlipressine
  • Terlipressinum
Product Ingredients
IngredientUNIICASInChI Key
Terlipressin acetate4U092XZF0KNot AvailableMLECZWUGJYWVAV-NSECCGHPSA-N
International/Other Brands
Glypressin (Ferring Pharmaceuticals) / Lucassin / Teripress (New Medicon Pharma)
Categories
UNII
7Z5X49W53P
CAS number
14636-12-5
Weight
Average: 1227.372
Monoisotopic: 1226.496097158
Chemical Formula
C52H74N16O15S2
InChI Key
BENFXAYNYRLAIU-QSVFAHTRSA-N
InChI
InChI=1S/C52H74N16O15S2/c53-17-5-4-9-31(45(76)60-23-41(57)72)63-51(82)38-10-6-18-68(38)52(83)37-27-85-84-26-36(61-44(75)25-59-43(74)24-58-42(73)22-54)50(81)65-34(20-29-11-13-30(69)14-12-29)48(79)64-33(19-28-7-2-1-3-8-28)47(78)62-32(15-16-39(55)70)46(77)66-35(21-40(56)71)49(80)67-37/h1-3,7-8,11-14,31-38,69H,4-6,9-10,15-27,53-54H2,(H2,55,70)(H2,56,71)(H2,57,72)(H,58,73)(H,59,74)(H,60,76)(H,61,75)(H,62,78)(H,63,82)(H,64,79)(H,65,81)(H,66,77)(H,67,80)/t31-,32-,33-,34-,35-,36-,37-,38-/m0/s1
IUPAC Name
(2S)-6-amino-2-{[(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-{2-[2-(2-aminoacetamido)acetamido]acetamido}-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carbonyl]pyrrolidin-2-yl]formamido}-N-(carbamoylmethyl)hexanamide
SMILES
NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSSC[C@H](NC(=O)CNC(=O)CNC(=O)CN)C(=O)N[C@@H](CC2=CC=C(O)C=C2)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1)C(=O)NCC(N)=O

Pharmacology

Indication

Commonly used to stop bleeding of varices in the food pipe (oesophagus).

Pharmacodynamics

Terlipressin is a medicine similar to a naturally occurring hormone present in the body, known as antidiuretic hormone (ADH) or vasopressin. ADH has two main effects in the body. Firstly, it causes narrowing of blood vessels (vasoconstriction), thereby limiting blood flow to a particular area of the body. It also acts on receptors in the kidney to retain water in the body, which helps to prevent excessive loss of water in the urine.

Mechanism of action

Terlipressin, an analogue of vasopressin, acts on three different receptors, vasopressin receptor V1a (which initiates vasoconstriction, liver gluconeogenesis, platelet aggregation and release of factor VIII), vasopressin receptor V1b (which mediates corticotrophin secretion from the pituitary) and vasopressin receptor V2 which controls free water reabsorption in the renal medullar. The binding of terlipressin to the V2 receptor activates adenylate cyclase which causes the release of aquaporin 2 channels into the cells lining the renal medullar duct. This allows water to be reabsorbed down an osmotic gradient so the urine is more concentrated.

TargetActionsOrganism
AVasopressin V2 receptor
agonist
Human
UVasopressin V1b receptorNot AvailableHuman
UVasopressin V1a receptor
stimulator
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

Approximately 30%

Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Terlipressin.
AcemetacinThe therapeutic efficacy of Terlipressin can be decreased when used in combination with Acemetacin.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Terlipressin.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Terlipressin.
AliskirenTerlipressin may increase the hypotensive activities of Aliskiren.
AlprenololAlprenolol may increase the hypotensive activities of Terlipressin.
AmbrisentanTerlipressin may increase the hypotensive activities of Ambrisentan.
AmifostineTerlipressin may increase the hypotensive activities of Amifostine.
AmiodaroneThe risk or severity of QTc prolongation can be increased when Terlipressin is combined with Amiodarone.
AmitriptylineThe risk or severity of QTc prolongation can be increased when Amitriptyline is combined with Terlipressin.
Food Interactions
Not Available

References

General References
  1. Pesaturo AB, Jennings HR, Voils SA: Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother. 2006 Dec;40(12):2170-7. Epub 2006 Dec 5. [PubMed:17148649]
  2. Klein M, Weksler N, Borer A, Koyfman L, Kesslin J, Gurman GM: Terlipressin facilitates transport of septic patients treated with norepinephrine. Isr Med Assoc J. 2006 Oct;8(10):691-3. [PubMed:17125115]
  3. Leone M, Charvet A, Delmas A, Albanese J, Martin C, Boyle WA: Terlipressin: a new therapeutic for calcium-channel blockers overdose. J Crit Care. 2005 Mar;20(1):114-5. [PubMed:16015526]
  4. Matok I, Vard A, Efrati O, Rubinshtein M, Vishne T, Leibovitch L, Adam M, Barzilay Z, Paret G: Terlipressin as rescue therapy for intractable hypotension due to septic shock in children. Shock. 2005 Apr;23(4):305-10. [PubMed:15803052]
  5. Kam PC, Williams S, Yoong FF: Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia. 2004 Oct;59(10):993-1001. [PubMed:15488059]
External Links
Human Metabolome Database
HMDB0015569
PubChem Compound
72081
PubChem Substance
46504626
ChemSpider
65067
ChEBI
135905
ChEMBL
CHEMBL2135460
Therapeutic Targets Database
DAP000058
PharmGKB
PA164781020
Wikipedia
Terlipressin
ATC Codes
H01BA04 — Terlipressin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentHepatorenal Syndrome Type 11
2CompletedPreventionHepatectomy, Surgical Blood Loss, Terlipressin1
2CompletedTreatmentBlood Loss / Terlipressin1
2CompletedTreatmentCompensated Cirrhosis and Portal Hypertension1
2CompletedTreatmentHemodynamics, Liver, Terlipressin1
2CompletedTreatmentShock, Septic1
2RecruitingTreatmentAscites Hepatic / Liver Cirrhosis1
2RecruitingTreatmentHepatic Failure / Liver Resection1
2RecruitingTreatmentPortal Vein Pressure1
2RecruitingTreatmentTerlipressin Adverse Reaction / Transplantation, Liver1
2Unknown StatusSupportive CareShock, Septic1
2WithdrawnPreventionRenal Failure1
2, 3CompletedNot AvailableAscites / Liver Cirrhosis1
2, 3CompletedTreatmentLiver Cirrhosis / Shock, Septic1
2, 3RecruitingTreatmentResolution of Septic Shock With Terlipressin1
3CompletedTreatmentHepatorenal Syndrome Type 1 / HRS1
3CompletedTreatmentHepatorenal Syndrome2
3CompletedTreatmentLiver Cirrhosis1
3CompletedTreatmentSafety and Efficacy of Terlipressin and Noradrenaline and Predictive Factors of Response in Type 2 HRS1
3Not Yet RecruitingPreventionBronchial Endoscopy1
3RecruitingTreatmentHepatorenal Syndrome1
3RecruitingTreatmentRefractory Shock / Shock, Septic1
3TerminatedTreatmentSepsis-associated Hypotension / Shock, Septic1
4Active Not RecruitingTreatmentHepatorenal Syndrome Type I / Liver Cirrhosis1
4CompletedPreventionAcute Kidney Injury (AKI) / NGAL / Terlipressin / Transplantation, Liver1
4CompletedTreatmentGastric and Esophageal Varices1
4CompletedTreatmentHaematemesis / Liver Cirrhosis / Melena / Portal Hypertension1
4CompletedTreatmentHemorrhage / Portal Hypertension / Varices, Esophageal1
4CompletedTreatmentVariceal Bleeding, Cirrhosis1
4CompletedTreatmentVasoconstrictor Choice on Acute Variceal Bleeding1
4RecruitingPreventionHepatorenal Syndrome1
4RecruitingTreatmentShock, Septic1
4SuspendedTreatmentHepatorenal Syndrome / Liver Cirrhosis1
4Unknown StatusTreatmentEsophageal Variceal Rebleeding1
Not AvailableCompletedTreatmentAcute on Chronic Liver Failure1
Not AvailableCompletedTreatmentCirrhosis With Septic Shock2
Not AvailableCompletedTreatmentHepatorenal Syndrome1
Not AvailableCompletedTreatmentLiver Cirrhosis1
Not AvailableNot Yet RecruitingTreatmentEsophageal and Gastric Varices / Gastroesophageal variceal hemorrhage prophylaxis / Haemorrhage / Liver Cirrhosis / Portal Hypertension1
Not AvailableRecruitingPreventionArterial Hypotension1
Not AvailableRecruitingTreatmentAcute Variceal Bleeding1
Not AvailableUnknown StatusNot AvailableEsophageal and Gastric Varices / Hemorrhage / Liver Cirrhosis1
Not AvailableUnknown StatusTreatmentShock, Septic1
Not AvailableUnknown StatusTreatmentShock, Septic / Terlipressin1
Not AvailableWithdrawnTreatmentHepatorenal Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.167 mg/mLALOGPS
logP-1.6ALOGPS
logP-10ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)9.43ChemAxon
pKa (Strongest Basic)10.26ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count16ChemAxon
Polar Surface Area512.85 Å2ChemAxon
Rotatable Bond Count25ChemAxon
Refractivity305.18 m3·mol-1ChemAxon
Polarizability123.88 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7085
Blood Brain Barrier-0.8855
Caco-2 permeable-0.7797
P-glycoprotein substrateSubstrate0.7307
P-glycoprotein inhibitor INon-inhibitor0.8042
P-glycoprotein inhibitor IINon-inhibitor0.8977
Renal organic cation transporterNon-inhibitor0.8004
CYP450 2C9 substrateNon-substrate0.8292
CYP450 2D6 substrateNon-substrate0.7878
CYP450 3A4 substrateNon-substrate0.5247
CYP450 1A2 substrateNon-inhibitor0.9358
CYP450 2C9 inhibitorNon-inhibitor0.766
CYP450 2D6 inhibitorNon-inhibitor0.8606
CYP450 2C19 inhibitorNon-inhibitor0.7565
CYP450 3A4 inhibitorNon-inhibitor0.7185
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8301
Ames testNon AMES toxic0.736
CarcinogenicityNon-carcinogens0.8513
BiodegradationNot ready biodegradable0.9261
Rat acute toxicity2.9218 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8955
hERG inhibition (predictor II)Inhibitor0.6764
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Cyclic peptides / Proline and derivatives / Macrolactams / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Pyrrolidinecarboxamides / N-acylpyrrolidines / 1-hydroxy-2-unsubstituted benzenoids / Benzene and substituted derivatives / N-acyl amines
show 11 more
Substituents
Polypeptide / Cyclic alpha peptide / Proline or derivatives / Macrolactam / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / N-substituted-alpha-amino acid / Alpha-amino acid or derivatives / N-acylpyrrolidine / Pyrrolidine carboxylic acid or derivatives
show 31 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Vasopressin receptor activity
Specific Function
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
Gene Name
AVPR2
Uniprot ID
P30518
Uniprot Name
Vasopressin V2 receptor
Molecular Weight
40278.57 Da
References
  1. Boson WL, Della Manna T, Damiani D, Miranda DM, Gadelha MR, Liberman B, Correa H, Romano-Silva MA, Friedman E, Silva FF, Ribeiro PA, De Marco L: Novel vasopressin type 2 (AVPR2) gene mutations in Brazilian nephrogenic diabetes insipidus patients. Genet Test. 2006 Fall;10(3):157-62. [PubMed:17020465]
  2. Slusarz MJ, Slusarz R, Ciarkowski J: Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: molecular dynamics simulation of the agonist-bound state in the membrane-aqueous system. Biopolymers. 2006 Apr 5;81(5):321-38. [PubMed:16333859]
  3. Bouley R, Hawthorn G, Russo LM, Lin HY, Ausiello DA, Brown D: Aquaporin 2 (AQP2) and vasopressin type 2 receptor (V2R) endocytosis in kidney epithelial cells: AQP2 is located in 'endocytosis-resistant' membrane domains after vasopressin treatment. Biol Cell. 2006 Apr;98(4):215-32. [PubMed:16563128]
  4. Yi X, Bouley R, Lin HY, Bechoua S, Sun TX, Del Re E, Shioda T, Raychowdhury MK, Lu HA, Abou-Samra AB, Brown D, Ausiello DA: Alix (AIP1) is a vasopressin receptor (V2R)-interacting protein that increases lysosomal degradation of the V2R. Am J Physiol Renal Physiol. 2007 May;292(5):F1303-13. Epub 2007 Feb 6. [PubMed:17287200]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vasopressin receptor activity
Specific Function
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
Gene Name
AVPR1B
Uniprot ID
P47901
Uniprot Name
Vasopressin V1b receptor
Molecular Weight
46970.345 Da
References
  1. Young WS, Li J, Wersinger SR, Palkovits M: The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience. 2006 Dec 28;143(4):1031-9. Epub 2006 Oct 4. [PubMed:17027167]
  2. Volpi S, Liu Y, Aguilera G: Vasopressin increases GAGA binding activity to the V1b receptor promoter through transactivation of the MAP kinase pathway. J Mol Endocrinol. 2006 Jun;36(3):581-90. [PubMed:16720725]
  3. Wersinger SR, Caldwell HK, Christiansen M, Young WS 3rd: Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav. 2007 Oct;6(7):653-60. Epub 2006 Dec 20. [PubMed:17284170]
  4. Slusarz MJ, Gieldon A, Slusarz R, Ciarkowski J: Analysis of interactions responsible for vasopressin binding to human neurohypophyseal hormone receptors-molecular dynamics study of the activated receptor-vasopressin-G(alpha) systems. J Pept Sci. 2006 Mar;12(3):180-9. [PubMed:16114100]
  5. Jurkevich A, Berghman LR, Cornett LE, Kuenzel WJ: Characterization and immunohistochemical visualization of the vasotocin VT2 receptor in the pituitary gland of the chicken, Gallus gallus. Gen Comp Endocrinol. 2005 Aug;143(1):82-91. Epub 2005 Mar 23. [PubMed:15993108]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Stimulator
General Function
Vasopressin receptor activity
Specific Function
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 behavi...
Gene Name
AVPR1A
Uniprot ID
P37288
Uniprot Name
Vasopressin V1a receptor
Molecular Weight
46799.105 Da
References
  1. Hiroyama M, Wang S, Aoyagi T, Oikawa R, Sanbe A, Takeo S, Tanoue A: Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. Eur J Pharmacol. 2007 Mar 22;559(2-3):89-97. Epub 2006 Dec 29. [PubMed:17275806]
  2. Liedman R, Grant L, Igidbashian S, James I, McLeod A, Skillern L, Akerlund M: Intrauterine pressure, ischemia markers, and experienced pain during administration of a vasopressin V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea. Acta Obstet Gynecol Scand. 2006;85(2):207-11. [PubMed:16532916]
  3. Adikesavan NV, Mahmood SS, Stanley N, Xu Z, Wu N, Thibonnier M, Shoham M: A C-terminal segment of the V1R vasopressin receptor is unstructured in the crystal structure of its chimera with the maltose-binding protein. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 Apr 1;61(Pt 4):341-5. Epub 2005 Mar 24. [PubMed:16511036]
  4. Hammock EA, Lim MM, Nair HP, Young LJ: Association of vasopressin 1a receptor levels with a regulatory microsatellite and behavior. Genes Brain Behav. 2005 Jul;4(5):289-301. [PubMed:16011575]
  5. Aoyagi T, Birumachi J, Hiroyama M, Fujiwara Y, Sanbe A, Yamauchi J, Tanoue A: Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice. Endocrinology. 2007 May;148(5):2075-84. Epub 2007 Feb 15. [PubMed:17303660]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 04:54