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Identification
NameDegarelix
Accession NumberDB06699
TypeSmall Molecule
GroupsApproved
DescriptionDegarelix is used for the treatment of advanced prostate cancer. Degarelix is a synthetic peptide derivative drug which binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocks interaction with GnRH. This antagonism reduces luteinising hormone (LH) and follicle-stimulating hormone (FSH) which ultimately causes testosterone suppression. Reduction in testosterone is important in treating men with advanced prostate cancer. Chemically, it is a synthetic linear decapeptide amide with seven unnatural amino acids, five of which are D-amino acids. FDA approved on December 24, 2008.
Structure
Thumb
SynonymsNot Available
External Identifiers
  • FE200486
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FirmagonkitFerring Pharmaceuticals Inc.2009-03-02Not applicableUs
FirmagonPowder and solvent for solution for injection80 mgSubcutaneous useFerring Pharmaceuticals A/S2009-02-17Not applicableEu
FirmagonkitFerring Pharmaceuticals Inc.2009-03-02Not applicableUs
FirmagonPowder and solvent for solution for injection120 mgSubcutaneous useFerring Pharmaceuticals A/S2009-02-17Not applicableEu
Firmagonpowder for solution80 mgsubcutaneousFerring Inc2009-11-24Not applicableCanada
FirmagonPowder and solvent for solution for injection80 mgSubcutaneous useFerring Pharmaceuticals A/S2009-02-17Not applicableEu
Firmagonpowder for solution120 mgsubcutaneousFerring Inc2009-11-24Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Degarelix acetate hydrate
934246-14-7
Thumb
  • InChI Key: AUTFSFUMNFDPLH-KYMMNHPFSA-N
  • Monoisotopic Mass: 1690.769926417
  • Average Mass: 1692.311
DBSALT000037
Categories
UNIISX0XJI3A11
CAS number214766-78-6
WeightAverage: 1632.29
Monoisotopic: 1630.748797
Chemical FormulaC82H103ClN18O16
InChI KeyMEUCPCLKGZSHTA-XYAYPHGZSA-N
InChI
InChI=1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66+,67+,68+/m1/s1
IUPAC Name
(4S)-N-{4-[(2S)-2-{[(1R)-2-[4-(carbamoylamino)phenyl]-1-{[(1S)-1-{[(2S)-1-[(2S)-2-{[(1R)-1-carbamoylethyl]carbamoyl}pyrrolidin-1-yl]-1-oxo-6-[(propan-2-yl)amino]hexan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}ethyl]carbamoyl}-2-[(2S)-2-[(2R)-2-[(2R)-3-(4-chlorophenyl)-2-[(2R)-2-acetamido-3-(naphthalen-2-yl)propanamido]propanamido]-3-(pyridin-3-yl)propanamido]-3-hydroxypropanamido]ethyl]phenyl}-2,6-dioxo-1,3-diazinane-4-carboxamide
SMILES
CC(C)C[[email protected]](NC(=O)[C@@H](CC1=CC=C(NC(N)=O)C=C1)NC(=O)[[email protected]](CC1=CC=C(NC(=O)[C@@H]2CC(=O)NC(=O)N2)C=C1)NC(=O)[[email protected]](CO)NC(=O)[C@@H](CC1=CC=CN=C1)NC(=O)[C@@H](CC1=CC=C(Cl)C=C1)NC(=O)[C@@H](CC1=CC=C2C=CC=CC2=C1)NC(C)=O)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1CCC[[email protected]]1C(=O)N[[email protected]](C)C(N)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
KingdomOrganic compounds
Super ClassOrganic Polymers
ClassPolypeptides
Sub ClassNot Available
Direct ParentPolypeptides
Alternative Parents
Substituents
  • Polypeptide
  • Alpha peptide
  • Phenylalanine or derivatives
  • Leucine or derivatives
  • Proline or derivatives
  • N-acyl-alpha amino acid or derivatives
  • Alpha-amino acid amide
  • Serine or derivatives
  • Alanine or derivatives
  • N-substituted-alpha-amino acid
  • Alpha-amino acid or derivatives
  • N-phenylurea
  • Naphthalene
  • Amphetamine or derivatives
  • Anilide
  • Pyrrolidine-2-carboxamide
  • N-arylamide
  • Pyrrolidine carboxylic acid or derivatives
  • N-acylpyrrolidine
  • Chlorobenzene
  • Ureide
  • Halobenzene
  • Pyrimidone
  • Fatty amide
  • 1,3-diazinane
  • Fatty acyl
  • Aryl chloride
  • Monocyclic benzene moiety
  • Aryl halide
  • N-acyl-amine
  • Pyrimidine
  • Pyridine
  • Benzenoid
  • Acetamide
  • Tertiary carboxylic acid amide
  • Dicarboximide
  • Heteroaromatic compound
  • Pyrrolidine
  • Carboxamide group
  • Primary carboxylic acid amide
  • Secondary carboxylic acid amide
  • Urea
  • Amino acid or derivatives
  • Azacycle
  • Organoheterocyclic compound
  • Secondary amine
  • Carboxylic acid derivative
  • Secondary aliphatic amine
  • Organooxygen compound
  • Carbonyl group
  • Primary alcohol
  • Organic oxygen compound
  • Organic nitrogen compound
  • Alcohol
  • Hydrocarbon derivative
  • Organic oxide
  • Organonitrogen compound
  • Amine
  • Organochloride
  • Organohalogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationDegaralix is used for the management of advanced prostate cancer.
PharmacodynamicsDegarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes.
Mechanism of actionGnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible blinding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer.
Related Articles
AbsorptionDegarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days.
Volume of distribution

Central compartment: 8.88 – 11.4 L;
Peripheral compartment: 40.9 L

Protein binding90% of the drug is bound to plasma proteins.
Metabolism

70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes.

Route of eliminationFecal (70% to 80%) and renal (20%-30% of unchanged drug)
Half lifeTerminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days.
Clearance

Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.

ToxicityThe most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8352
Blood Brain Barrier-0.953
Caco-2 permeable-0.7556
P-glycoprotein substrateSubstrate0.8461
P-glycoprotein inhibitor INon-inhibitor0.6672
P-glycoprotein inhibitor IINon-inhibitor0.7791
Renal organic cation transporterNon-inhibitor0.8579
CYP450 2C9 substrateNon-substrate0.7299
CYP450 2D6 substrateNon-substrate0.8156
CYP450 3A4 substrateSubstrate0.6482
CYP450 1A2 substrateNon-inhibitor0.8566
CYP450 2C9 inhibitorNon-inhibitor0.6493
CYP450 2D6 inhibitorNon-inhibitor0.8566
CYP450 2C19 inhibitorNon-inhibitor0.7291
CYP450 3A4 inhibitorNon-inhibitor0.5961
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8478
Ames testNon AMES toxic0.652
CarcinogenicityNon-carcinogens0.7848
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7005 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8534
hERG inhibition (predictor II)Inhibitor0.5235
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Kit
Powder and solvent for solution for injectionSubcutaneous use120 mg
Powder and solvent for solution for injectionSubcutaneous use80 mg
Powder for solutionsubcutaneous120 mg
Powder for solutionsubcutaneous80 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2286190 No2007-01-092018-04-13Canada
US5925730 No2001-05-182021-05-18Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0041 mg/mLALOGPS
logP2.66ALOGPS
logP0.18ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)10.55ChemAxon
pKa (Strongest Basic)11.16ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count18ChemAxon
Hydrogen Donor Count17ChemAxon
Polar Surface Area512.87 Å2ChemAxon
Rotatable Bond Count41ChemAxon
Refractivity431.13 m3·mol-1ChemAxon
Polarizability168.98 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Carin WINDERSTROM, “KIT AND METHOD FOR PREPARATION OF A DEGARELIX SOLUTION.” U.S. Patent US20100286603, issued November 11, 2010.

US20100286603
General References
  1. Steinberg M: Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther. 2009;31 Pt 2:2312-31. doi: 10.1016/j.clinthera.2009.11.009. [PubMed:20110043 ]
  2. Persson BE, Kold Olesen T, Jensen JK: Degarelix: a new approach for the treatment of prostate cancer. Neuroendocrinology. 2009;90(3):235-44. doi: 10.1159/000228832. Epub 2009 Jul 14. [PubMed:19602868 ]
External Links
ATC CodesL02BX02
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (448 KB)
MSDSDownload (479 KB)
Interactions
Drug Interactions
Drug
AmiodaroneDegarelix may increase the QTc-prolonging activities of Amiodarone.
AnagrelideDegarelix may increase the QTc-prolonging activities of Anagrelide.
Arsenic trioxideDegarelix may increase the QTc-prolonging activities of Arsenic trioxide.
ArtemetherDegarelix may increase the QTc-prolonging activities of Artemether.
AsenapineDegarelix may increase the QTc-prolonging activities of Asenapine.
AzithromycinDegarelix may increase the QTc-prolonging activities of Azithromycin.
BedaquilineDegarelix may increase the QTc-prolonging activities of Bedaquiline.
CeritinibDegarelix may increase the QTc-prolonging activities of Ceritinib.
ChloroquineDegarelix may increase the QTc-prolonging activities of Chloroquine.
ChlorpromazineDegarelix may increase the QTc-prolonging activities of Chlorpromazine.
CiprofloxacinDegarelix may increase the QTc-prolonging activities of Ciprofloxacin.
CisaprideDegarelix may increase the QTc-prolonging activities of Cisapride.
CitalopramDegarelix may increase the QTc-prolonging activities of Citalopram.
ClarithromycinDegarelix may increase the QTc-prolonging activities of Clarithromycin.
ClozapineDegarelix may increase the QTc-prolonging activities of Clozapine.
CrizotinibDegarelix may increase the QTc-prolonging activities of Crizotinib.
DisopyramideDegarelix may increase the QTc-prolonging activities of Disopyramide.
DofetilideDegarelix may increase the QTc-prolonging activities of Dofetilide.
DolasetronDegarelix may increase the QTc-prolonging activities of Dolasetron.
DomperidoneDegarelix may increase the QTc-prolonging activities of Domperidone.
DronedaroneDegarelix may increase the QTc-prolonging activities of Dronedarone.
DroperidolDegarelix may increase the QTc-prolonging activities of Droperidol.
EliglustatDegarelix may increase the QTc-prolonging activities of Eliglustat.
ErythromycinDegarelix may increase the QTc-prolonging activities of Erythromycin.
EscitalopramDegarelix may increase the QTc-prolonging activities of Escitalopram.
FlecainideDegarelix may increase the QTc-prolonging activities of Flecainide.
FluoxetineDegarelix may increase the QTc-prolonging activities of Fluoxetine.
FlupentixolDegarelix may increase the QTc-prolonging activities of Flupentixol.
Gadobenic acidDegarelix may increase the QTc-prolonging activities of Gadobenic acid.
GemifloxacinDegarelix may increase the QTc-prolonging activities of Gemifloxacin.
GoserelinDegarelix may increase the QTc-prolonging activities of Goserelin.
GranisetronDegarelix may increase the QTc-prolonging activities of Granisetron.
HaloperidolDegarelix may increase the QTc-prolonging activities of Haloperidol.
IbutilideDegarelix may increase the QTc-prolonging activities of Ibutilide.
IloperidoneDegarelix may increase the QTc-prolonging activities of Iloperidone.
LenvatinibDegarelix may increase the QTc-prolonging activities of Lenvatinib.
LeuprolideDegarelix may increase the QTc-prolonging activities of Leuprolide.
LevofloxacinDegarelix may increase the QTc-prolonging activities of Levofloxacin.
LopinavirDegarelix may increase the QTc-prolonging activities of Lopinavir.
LumefantrineDegarelix may increase the QTc-prolonging activities of Lumefantrine.
MethadoneDegarelix may increase the QTc-prolonging activities of Methadone.
MifepristoneMifepristone may increase the QTc-prolonging activities of Degarelix.
MoxifloxacinDegarelix may increase the QTc-prolonging activities of Moxifloxacin.
NilotinibDegarelix may increase the QTc-prolonging activities of Nilotinib.
OfloxacinDegarelix may increase the QTc-prolonging activities of Ofloxacin.
OndansetronDegarelix may increase the QTc-prolonging activities of Ondansetron.
PaliperidoneDegarelix may increase the QTc-prolonging activities of Paliperidone.
PanobinostatDegarelix may increase the QTc-prolonging activities of Panobinostat.
PazopanibDegarelix may increase the QTc-prolonging activities of Pazopanib.
PentamidineDegarelix may increase the QTc-prolonging activities of Pentamidine.
PerflutrenDegarelix may increase the QTc-prolonging activities of Perflutren.
PimozideDegarelix may increase the QTc-prolonging activities of Pimozide.
PrimaquineDegarelix may increase the QTc-prolonging activities of Primaquine.
ProcainamideDegarelix may increase the QTc-prolonging activities of Procainamide.
PromazineDegarelix may increase the QTc-prolonging activities of Promazine.
PropafenoneDegarelix may increase the QTc-prolonging activities of Propafenone.
QuetiapineDegarelix may increase the QTc-prolonging activities of Quetiapine.
QuinidineDegarelix may increase the QTc-prolonging activities of Quinidine.
QuinineDegarelix may increase the QTc-prolonging activities of Quinine.
SaquinavirDegarelix may increase the QTc-prolonging activities of Saquinavir.
SotalolDegarelix may increase the QTc-prolonging activities of Sotalol.
SulfisoxazoleDegarelix may increase the QTc-prolonging activities of Sulfisoxazole.
TelavancinDegarelix may increase the QTc-prolonging activities of Telavancin.
TelithromycinDegarelix may increase the QTc-prolonging activities of Telithromycin.
TetrabenazineDegarelix may increase the QTc-prolonging activities of Tetrabenazine.
ThioridazineDegarelix may increase the QTc-prolonging activities of Thioridazine.
ToremifeneDegarelix may increase the QTc-prolonging activities of Toremifene.
VandetanibDegarelix may increase the QTc-prolonging activities of Vandetanib.
VemurafenibDegarelix may increase the QTc-prolonging activities of Vemurafenib.
ZiprasidoneDegarelix may increase the QTc-prolonging activities of Ziprasidone.
ZuclopenthixolDegarelix may increase the QTc-prolonging activities of Zuclopenthixol.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Peptide binding
Specific Function:
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.
Gene Name:
GNRHR
Uniprot ID:
P30968
Molecular Weight:
37730.355 Da
References
  1. Steinberg M: Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther. 2009;31 Pt 2:2312-31. doi: 10.1016/j.clinthera.2009.11.009. [PubMed:20110043 ]
  2. Kirby RS, Fitzpatrick JM, Clarke N: Abarelix and other gonadotrophin-releasing hormone antagonists in prostate cancer. BJU Int. 2009 Dec;104(11):1580-4. doi: 10.1111/j.1464-410X.2009.08924.x. [PubMed:20053189 ]
  3. Anderson J: Degarelix: a novel gonadotropin-releasing hormone blocker for the treatment of prostate cancer. Future Oncol. 2009 May;5(4):433-43. doi: 10.2217/fon.09.24. [PubMed:19450172 ]
  4. Samant MP, Miller C, Hong DJ, Koerber SC, Croston G, Rivier CL, Rivier JE: Synthesis and biological activity of GnRH antagonists modified at position 3 with 3-(2-methoxy-5-pyridyl)-alanine. J Pept Res. 2005 Feb;65(2):284-91. [PubMed:15705170 ]
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Drug created on May 06, 2010 10:15 / Updated on September 30, 2016 02:26