Degarelix

Identification

Name
Degarelix
Accession Number
DB06699
Type
Small Molecule
Groups
Approved
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.

Structure
Thumb
Synonyms
Not Available
External IDs
FE200486
Product Ingredients
IngredientUNIICASInChI Key
Degarelix acetate hydrateEXT215F4ZU 934246-14-7AUTFSFUMNFDPLH-KYMMNHPFSA-N
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FirmagonPowder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-11-24Not applicableCanada
FirmagonInjection, powder, for solution120 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
FirmagonKitFerring Pharmaceuticals2009-03-02Not applicableUs
FirmagonPowder, for solution120 mgSubcutaneousFerring Pharmaceuticals2009-11-24Not applicableCanada
FirmagonInjection, powder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
FirmagonInjection, powder, for solution80 mgSubcutaneousFerring Pharmaceuticals2009-02-17Not applicableEu
FirmagonKitFerring Pharmaceuticals2009-03-02Not applicableUs
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
SX0XJI3A11
CAS number
214766-78-6
Weight
Average: 1632.29
Monoisotopic: 1630.748797
Chemical Formula
C82H103ClN18O16
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[[email protected]](NC(=O)[[email protected]@H](CC1=CC=C(NC(N)=O)C=C1)NC(=O)[[email protected]](CC1=CC=C(NC(=O)[[email protected]@H]2CC(=O)NC(=O)N2)C=C1)NC(=O)[[email protected]](CO)NC(=O)[[email protected]@H](CC1=CC=CN=C1)NC(=O)[[email protected]@H](CC1=CC=C(Cl)C=C1)NC(=O)[[email protected]@H](CC1=CC=C2C=CC=CC2=C1)NC(C)=O)C(=O)N[[email protected]@H](CCCCNC(C)C)C(=O)N1CCC[[email protected]]1C(=O)N[[email protected]](C)C(N)=O

Pharmacology

Indication

Degaralix is used for the management of advanced prostate cancer.

Structured Indications
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

GnRH 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.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Human
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.

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
DrugInteractionDrug group
AmiodaroneDegarelix may increase the QTc-prolonging activities of Amiodarone.Approved, Investigational
AnagrelideDegarelix may increase the QTc-prolonging activities of Anagrelide.Approved
Arsenic trioxideDegarelix may increase the QTc-prolonging activities of Arsenic trioxide.Approved, Investigational
ArtemetherDegarelix may increase the QTc-prolonging activities of Artemether.Approved
AsenapineDegarelix may increase the QTc-prolonging activities of Asenapine.Approved
AzithromycinDegarelix may increase the QTc-prolonging activities of Azithromycin.Approved
BedaquilineDegarelix may increase the QTc-prolonging activities of Bedaquiline.Approved
CeritinibDegarelix may increase the QTc-prolonging activities of Ceritinib.Approved
ChloroquineDegarelix may increase the QTc-prolonging activities of Chloroquine.Approved, Vet Approved
ChlorpromazineDegarelix may increase the QTc-prolonging activities of Chlorpromazine.Approved, Vet Approved
CiprofloxacinDegarelix may increase the QTc-prolonging activities of Ciprofloxacin.Approved, Investigational
CisaprideDegarelix may increase the QTc-prolonging activities of Cisapride.Approved, Investigational, Withdrawn
CitalopramDegarelix may increase the QTc-prolonging activities of Citalopram.Approved
ClarithromycinDegarelix may increase the QTc-prolonging activities of Clarithromycin.Approved
ClozapineDegarelix may increase the QTc-prolonging activities of Clozapine.Approved
CrizotinibDegarelix may increase the QTc-prolonging activities of Crizotinib.Approved
DisopyramideDegarelix may increase the QTc-prolonging activities of Disopyramide.Approved
DofetilideDegarelix may increase the QTc-prolonging activities of Dofetilide.Approved
DolasetronDegarelix may increase the QTc-prolonging activities of Dolasetron.Approved
DomperidoneDegarelix may increase the QTc-prolonging activities of Domperidone.Approved, Investigational, Vet Approved
DronedaroneDegarelix may increase the QTc-prolonging activities of Dronedarone.Approved
DroperidolDegarelix may increase the QTc-prolonging activities of Droperidol.Approved, Vet Approved
EliglustatDegarelix may increase the QTc-prolonging activities of Eliglustat.Approved
ErythromycinDegarelix may increase the QTc-prolonging activities of Erythromycin.Approved, Vet Approved
EscitalopramDegarelix may increase the QTc-prolonging activities of Escitalopram.Approved, Investigational
FlecainideDegarelix may increase the QTc-prolonging activities of Flecainide.Approved, Withdrawn
FluoxetineDegarelix may increase the QTc-prolonging activities of Fluoxetine.Approved, Vet Approved
FlupentixolDegarelix may increase the QTc-prolonging activities of Flupentixol.Approved, Withdrawn
Gadobenic acidDegarelix may increase the QTc-prolonging activities of Gadobenic acid.Approved
GemifloxacinDegarelix may increase the QTc-prolonging activities of Gemifloxacin.Approved, Investigational
GoserelinDegarelix may increase the QTc-prolonging activities of Goserelin.Approved
GranisetronDegarelix may increase the QTc-prolonging activities of Granisetron.Approved, Investigational
HaloperidolDegarelix may increase the QTc-prolonging activities of Haloperidol.Approved
IbutilideDegarelix may increase the QTc-prolonging activities of Ibutilide.Approved
IloperidoneDegarelix may increase the QTc-prolonging activities of Iloperidone.Approved
LenvatinibDegarelix may increase the QTc-prolonging activities of Lenvatinib.Approved
LeuprolideDegarelix may increase the QTc-prolonging activities of Leuprolide.Approved, Investigational
LevofloxacinDegarelix may increase the QTc-prolonging activities of Levofloxacin.Approved, Investigational
LopinavirDegarelix may increase the QTc-prolonging activities of Lopinavir.Approved
LumefantrineDegarelix may increase the QTc-prolonging activities of Lumefantrine.Approved
MethadoneDegarelix may increase the QTc-prolonging activities of Methadone.Approved
MifepristoneMifepristone may increase the QTc-prolonging activities of Degarelix.Approved, Investigational
MoxifloxacinDegarelix may increase the QTc-prolonging activities of Moxifloxacin.Approved, Investigational
NilotinibDegarelix may increase the QTc-prolonging activities of Nilotinib.Approved, Investigational
OfloxacinDegarelix may increase the QTc-prolonging activities of Ofloxacin.Approved
OndansetronDegarelix may increase the QTc-prolonging activities of Ondansetron.Approved
PaliperidoneDegarelix may increase the QTc-prolonging activities of Paliperidone.Approved
PanobinostatDegarelix may increase the QTc-prolonging activities of Panobinostat.Approved, Investigational
PazopanibDegarelix may increase the QTc-prolonging activities of Pazopanib.Approved
PentamidineDegarelix may increase the QTc-prolonging activities of Pentamidine.Approved
PerflutrenDegarelix may increase the QTc-prolonging activities of Perflutren.Approved
PimozideDegarelix may increase the QTc-prolonging activities of Pimozide.Approved
PrimaquineDegarelix may increase the QTc-prolonging activities of Primaquine.Approved
ProcainamideDegarelix may increase the QTc-prolonging activities of Procainamide.Approved
PromazineDegarelix may increase the QTc-prolonging activities of Promazine.Approved, Vet Approved
PropafenoneDegarelix may increase the QTc-prolonging activities of Propafenone.Approved
QuetiapineDegarelix may increase the QTc-prolonging activities of Quetiapine.Approved
QuinidineDegarelix may increase the QTc-prolonging activities of Quinidine.Approved
QuinineDegarelix may increase the QTc-prolonging activities of Quinine.Approved
SaquinavirDegarelix may increase the QTc-prolonging activities of Saquinavir.Approved, Investigational
SotalolDegarelix may increase the QTc-prolonging activities of Sotalol.Approved
SulfisoxazoleDegarelix may increase the QTc-prolonging activities of Sulfisoxazole.Approved, Vet Approved
TelavancinDegarelix may increase the QTc-prolonging activities of Telavancin.Approved
TelithromycinDegarelix may increase the QTc-prolonging activities of Telithromycin.Approved
TetrabenazineDegarelix may increase the QTc-prolonging activities of Tetrabenazine.Approved
ThioridazineDegarelix may increase the QTc-prolonging activities of Thioridazine.Withdrawn
ToremifeneDegarelix may increase the QTc-prolonging activities of Toremifene.Approved, Investigational
VandetanibDegarelix may increase the QTc-prolonging activities of Vandetanib.Approved
VemurafenibDegarelix may increase the QTc-prolonging activities of Vemurafenib.Approved
ZiprasidoneDegarelix may increase the QTc-prolonging activities of Ziprasidone.Approved
ZuclopenthixolDegarelix may increase the QTc-prolonging activities of Zuclopenthixol.Approved, Investigational
Food Interactions
Not 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
KEGG Drug
D08901
ChemSpider
17292756
BindingDB
50102450
ChEBI
135961
ChEMBL
CHEMBL415606
PharmGKB
PA165958373
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Degarelix
ATC Codes
L02BX02 — Degarelix
AHFS Codes
  • 10:00
PDB Entries
Not Available
FDA label
Download (448 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingBasic ScienceNormal Healthy Volunteers1
1Active Not RecruitingBasic ScienceProstate Cancer1
1RecruitingNot AvailableProstate Cancer1
1, 2Active Not RecruitingTreatmentProstate Cancer Adenocarcinoma in Situ1
1, 2RecruitingTreatmentAdenocarcinoma, Prostate / Stage I Prostate Cancer / Stage IIA Prostate Cancer / Stage IIB Prostate Cancer / Stage III Prostate Cancer1
2Active Not RecruitingTreatmentBreast Cancer Invasive Nos1
2Active Not RecruitingTreatmentMetastatic Castration Sensitive Prostate Cancer1
2Active Not RecruitingTreatmentProstate Cancer4
2CompletedTreatmentBenign Prostatic Hypertrophy (BPH)1
2CompletedTreatmentLower Urinary Tract Symptoms (LUTS)1
2CompletedTreatmentProstate Cancer12
2CompletedTreatmentProstatic Neoplasms1
2Not Yet RecruitingTreatmentAndrogen Antagonists / Neoadjuvant Therapy / Prostate Cancer / Prostatectomy1
2RecruitingSupportive CareAdenocarcinoma of the Prostate / Recurrent Prostate Cancer / Stage III Prostate Cancer / Stage IV Prostate Cancer1
2RecruitingTreatmentAdenocarcinoma, Prostate1
2RecruitingTreatmentMetastatic Prostatic Adenocarcinoma1
2RecruitingTreatmentProstate Cancer2
2RecruitingTreatmentProstatic Neoplasms1
2RecruitingTreatmentStage III Prostate Adenocarcinoma / Stage III Prostate Cancer / Stage IV Prostate Adenocarcinoma / Stage IV Prostate Cancer1
2TerminatedTreatmentProstate Cancer3
2TerminatedTreatmentProstatic Neoplasms1
2Unknown StatusTreatmentProstate Neoplasms1
2WithdrawnTreatmentLocalized Prostate Cancer / Prostate Cancer1
2, 3CompletedTreatmentProstate Cancer3
3CompletedTreatmentEndometriosis1
3CompletedTreatmentInfertilities / OHSS / Polycystic Ovarian Syndrome1
3CompletedTreatmentProstate Cancer14
3RecruitingTreatmentProstate Cancer3
3TerminatedTreatmentProstate Cancer2
3WithdrawnTreatmentProstate Cancer1
4RecruitingNot AvailableCardiovascular Disease (CVD) / Prostatic Neoplasms1
4RecruitingOtherProstate Cancer1
4RecruitingTreatmentProstate Cancer1
4TerminatedTreatmentProstate Cancer Recurrent1
Not AvailableActive Not RecruitingNot AvailableAdvanced Hormone Dependent Prostate Cancer1
Not AvailableActive Not RecruitingNot AvailableAdvanced Hormone Sensitive Prostate Cancer1
Not AvailableActive Not RecruitingTreatmentProstate Cancer / Prostatic Adenocarcinoma1
Not AvailableActive Not RecruitingTreatmentStage IV Prostate Cancer1
Not AvailableCompletedTreatmentAdenocarcinoma, Prostate / Stage IIA Prostate Cancer / Stage IIB Prostate Cancer / Stage III Prostate Cancer / Stage IV Prostate Cancer1
Not AvailableCompletedTreatmentProstate Cancer1
Not AvailableRecruitingNot AvailableAdvanced Prostate Cancer1
Not AvailableRecruitingNot AvailableProstate Cancer2
Not AvailableRecruitingDiagnosticBMI >30 kg/m2 / Fertility1
Not AvailableUnknown StatusNot AvailableProstate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous120 mg
Injection, powder, for solutionSubcutaneous80 mg
Kit
Powder, for solutionSubcutaneous120 mg
Powder, for solutionSubcutaneous80 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2286190 No2007-01-092018-04-13Canada
US5925730 No2001-05-182021-05-18Us
US9579359 No2009-02-102029-02-10Us
US9415085 No2012-04-272032-04-27Us

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

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
Peptides / Phenylalanine and derivatives / Leucine and derivatives / Proline and derivatives / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Serine and derivatives / Alanine and derivatives / Amphetamines and derivatives / N-phenylureas
show 25 more
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
show 51 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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...
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 September 01, 2017 11:30