Degarelix

Identification

Name
Degarelix
Accession Number
DB06699
Description

Degarelix 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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 1632.29
Monoisotopic: 1630.748797
Chemical Formula
C82H103ClN18O16
Synonyms
  • Degarelix
External IDs
  • FE200486

Pharmacology

Indication

Degaralix is used for the management of advanced prostate cancer.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Degarelix 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 action

Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Humans
Absorption

Degarelix 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 binding

90% 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 elimination

Fecal (70% to 80%) and renal (20%-30% of unchanged drug)

Half-life

Terminal 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.

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

The 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcebutololThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Acebutolol.
AcrivastineThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Acrivastine.
AdenosineThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Adenosine.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Degarelix.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Degarelix.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Degarelix.
AmantadineThe risk or severity of QTc prolongation can be increased when Amantadine is combined with Degarelix.
AmifampridineThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Amifampridine.
AmiodaroneThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Amiodarone.
AmisulprideThe risk or severity of QTc prolongation can be increased when Amisulpride is combined with Degarelix.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Degarelix acetate hydrateEXT215F4ZU934246-14-7AUTFSFUMNFDPLH-KYMMNHPFSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FirmagonPowder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-11-24Not applicableCanada
FirmagonInjection, powder, for solution120 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
FirmagonPowder, metered20 mg/1mLSubcutaneousFerring Pharmaceuticals2009-03-022015-03-31Us
FirmagonPowder, metered40 mg/1mLSubcutaneousFerring Pharmaceuticals2009-03-022015-03-31Us
FirmagonPowder, for solution120 mgSubcutaneousFerring Pharmaceuticals2009-11-24Not applicableCanada
FirmagonInjection, powder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
Firmagon20 mg/1mLSubcutaneousFerring Pharmaceuticals Inc.2009-03-02Not applicableUs
FirmagonInjection, powder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
Firmagon40 mg/1mLSubcutaneousFerring Pharmaceuticals Inc.2009-03-02Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L02BX02 — Degarelix
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Peptides / Phenylalanine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Serine and derivatives / Alpha amino acid amides / Alanine and derivatives / N-phenylureas / Naphthalenes
show 26 more
Substituents
1,3-diazinane / Acetamide / Alanine or derivatives / Alcohol / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid or derivatives / Amphetamine or derivatives
show 54 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
SX0XJI3A11
CAS number
214766-78-6
InChI Key
MEUCPCLKGZSHTA-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[C@H](NC(=O)[C@@H](CC1=CC=C(NC(N)=O)C=C1)NC(=O)[C@H](CC1=CC=C(NC(=O)[C@@H]2CC(=O)NC(=O)N2)C=C1)NC(=O)[C@H](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[C@H]1C(=O)N[C@H](C)C(N)=O

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]
KEGG Drug
D08901
PubChem Compound
16136245
PubChem Substance
99443253
ChemSpider
17292756
BindingDB
50102450
RxNav
475230
ChEBI
135961
ChEMBL
CHEMBL415606
PharmGKB
PA165958373
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Degarelix
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
  • 92:40.00 — Gonadotropin-releasing Hormone Antagonists
FDA label
Download (448 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentProstate Cancer1
4CompletedOtherCardiovascular Heart Disease / Prostatic Neoplasms1
4RecruitingOtherProstate Cancer1
4RecruitingSupportive CareProstatic Neoplasms1
4SuspendedBasic ScienceAging / Menopause / Obesity, Abdominal / Weight Gain1
4TerminatedTreatmentRecurrent Prostate Cancer1
3Active Not RecruitingTreatmentProstate Cancer2
3CompletedTreatmentEndometriosis1
3CompletedTreatmentInfertility / OHSS / Polycystic Ovarian Syndrome1
3CompletedTreatmentProstate Cancer15

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous120 mg
Injection, powder, for solutionSubcutaneous80 mg
Powder, for solutionSubcutaneous120 mg
Powder, for solutionSubcutaneous80 mg
Powder, meteredSubcutaneous20 mg/1mL
Powder, meteredSubcutaneous40 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2286190No2007-01-092018-04-13Canada
US5925730No1999-07-202021-05-18Us
US9579359No2017-02-282029-02-10Us
US9415085No2016-08-162032-04-27Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not 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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
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...
Gene Name
GNRHR
Uniprot ID
P30968
Uniprot Name
Gonadotropin-releasing hormone receptor
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]

Drug created on May 06, 2010 10:15 / Updated on August 05, 2020 23:35

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