Degarelix

Identification

Summary

Degarelix is a GnRH receptor antagonist used in the management of advanced prostate cancer.

Brand Names

Firmagon

Generic Name

Degarelix

DrugBank Accession Number

DB06699

Background

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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Degarelix (DB06699)

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Weight

Average: 1632.29
Monoisotopic: 1630.748797

Chemical Formula

C₈₂H₁₀₃ClN₁₈O₁₆

Synonyms

• Degarelix

External IDs

• FE200486

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Pharmacology

Indication

In Canada and the US, degarelix is indicated for the treatment of advanced prostate cancer in patients requiring androgen deprivation therapy.^3,4 In the EU, it is more specifically indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer, and for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer, in combination with radiotherapy or as a neo-adjuvant prior to radiotherapy.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Advanced hormone dependent prostate cancer		••••••••••••	•••••		•••••••••• ••••••• ••• ••••••••
Used as adjunct in combination to treat	Advanced hormone dependent prostate cancer		••••••••••••	•••••		•••••••••• ••••••• ••• ••••••••
Treatment of	Advanced hormone dependent prostate cancer		••••••••••••			•••••••••• ••••••• ••• ••••••••
Treatment of	Advanced prostate cancer		••••••••••••			•••••••••• ••••••• ••• ••••••••

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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.

Target	Actions	Organism
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

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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).

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Acrivastine	The risk or severity of QTc prolongation can be increased when Degarelix is combined with Acrivastine.
Adenosine	The risk or severity of QTc prolongation can be increased when Degarelix is combined with Adenosine.
Ajmaline	The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Degarelix.
Alfuzosin	The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Degarelix.
Alimemazine	The risk or severity of QTc prolongation can be increased when Alimemazine is combined with Degarelix.

Food Interactions

No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Degarelix acetate hydrate	EXT215F4ZU	934246-14-7	AUTFSFUMNFDPLH-KYMMNHPFSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Firmagon	Injection, powder, for solution	120 mg	Subcutaneous	Ferring Pharmaceuticals	2016-09-08	Not applicable
Firmagon	Powder, for solution	80 mg / vial	Subcutaneous	Ferring Pharmaceuticals	2009-11-24	Not applicable
Firmagon	Powder, metered	20 mg/1mL	Subcutaneous	Ferring Pharmaceuticals	2009-03-02	2015-03-31
Firmagon	Injection, powder, for solution	80 mg	Subcutaneous	Ferring Pharmaceuticals	2016-09-08	Not applicable
Firmagon	Injection, powder, lyophilized, for solution; Kit	20 mg/1mL	Subcutaneous	Ferring Pharmaceuticals Inc.	2009-03-02	Not applicable

Categories

ATC Codes

L02BX02 — Degarelix

• L02BX — Other hormone antagonists and related agents
• L02B — HORMONE ANTAGONISTS AND RELATED AGENTS
• L02 — ENDOCRINE THERAPY
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Decreased GnRH Secretion
• Endocrine Therapy
• Gonadotropin Releasing Hormone Receptor Antagonists
• Gonadotropin-releasing Hormone Antagonists
• Gonadotropin-Releasing Hormone, antagonists & inhibitors
• Hormone Antagonists and Related Agents
• Peptides
• Potential QTc-Prolonging Agents
• QTc Prolonging Agents

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 / Amphetamines and derivatives / Anilides / Pyrrolidinecarboxamides / N-acylpyrrolidines / N-arylamides / Pyrimidones / N-acyl ureas / Chlorobenzenes / N-acyl amines / Diazinanes / Aryl chlorides / Pyridines and derivatives / Tertiary carboxylic acid amides / Acetamides / Heteroaromatic compounds / Dicarboximides / Secondary carboxylic acid amides / Primary carboxylic acid amides / Dialkylamines / Azacyclic compounds / Primary alcohols / Hydrocarbon derivatives / Organic oxides / Organochlorides / Organopnictogen compounds / Carbonyl compounds

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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 / Anilide / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Chlorobenzene / Dicarboximide / Fatty acyl / Fatty amide / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Leucine or derivatives / Monocyclic benzene moiety / N-acyl urea / N-acyl-alpha amino acid or derivatives / N-acyl-amine / N-acylpyrrolidine / N-arylamide / N-phenylurea / N-substituted-alpha-amino acid / Naphthalene / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Phenylalanine or derivatives / Polypeptide / Primary alcohol / Primary carboxylic acid amide / Proline or derivatives / Pyridine / Pyrimidine / Pyrimidone / Pyrrolidine / Pyrrolidine carboxylic acid or derivatives / Pyrrolidine-2-carboxamide / Secondary aliphatic amine / Secondary amine / Secondary carboxylic acid amide / Serine or derivatives / Tertiary carboxylic acid amide / Urea / Ureide

show 54 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

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. [Article]
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. [Article]
3. FDA Approved Drug Products: Firmagon (degarelix) powder for solution for subcutaneous injection (February 2020) [Link]
4. Health Canada Approved Drug Products: Firmagon (degarelix) powder for solution for subcutaneous injection [Link]
5. EMA Summary of Product Characteristics: Firmagon (degarelix) powder for solution for subcutaneous injection [Link]

External Links

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

FDA label

Download (448 KB)

MSDS

Download (479 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Other	Cardiovascular Disease (CVD) / Neoplasms of the Prostate	1
4	Completed	Treatment	Prostate Cancer	1
4	Recruiting	Basic Science	Aging / Hypoestrogenism / Menopause / Women	1
4	Recruiting	Basic Science	Aging / Menopause / Obesity, Abdominal / Weight Gain	1
4	Recruiting	Other	Prostate Cancer / Prostatic Hyperplasia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Parenteral; Subcutaneous	120 MG
Injection, powder, for solution	Parenteral; Subcutaneous	80 MG
Injection, powder, lyophilized, for solution; kit	Subcutaneous	20 mg/1mL
Injection, powder, lyophilized, for solution; kit	Subcutaneous	40 mg/1mL
Powder, for solution	Subcutaneous	120 mg / vial
Powder, for solution	Subcutaneous	80 mg / vial
Powder, metered	Subcutaneous	20 mg/1mL
Powder, metered	Subcutaneous	40 mg/1mL
Injection, powder, lyophilized, for solution	Subcutaneous	120 mg
Injection, powder, lyophilized, for solution	Subcutaneous	80 mg
Powder	Subcutaneous
Solution	Subcutaneous	88.200 mg
Injection, powder, for solution	Subcutaneous	120 mg
Injection, powder, for solution	Subcutaneous	80 mg
Powder	Subcutaneous	120 mg/1vial
Powder	Subcutaneous	80 mg/1vial

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2286190	No	2007-01-09	2018-04-13
US5925730	No	1999-07-20	2021-05-18
US9579359	No	2017-02-28	2029-02-10
US9415085	No	2016-08-16	2032-04-27
US10695398	No	2020-06-30	2032-04-27
US10729739	No	2020-08-04	2029-02-10
US10973870	No	2021-04-13	2029-02-10
US11766468	No	2012-04-27	2032-04-27
US11826397	No	2012-04-27	2032-04-27

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0041 mg/mL	ALOGPS
logP	2.66	ALOGPS
logP	0.18	Chemaxon
logS	-5.6	ALOGPS
pKa (Strongest Acidic)	10.55	Chemaxon
pKa (Strongest Basic)	11.16	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	18	Chemaxon
Hydrogen Donor Count	17	Chemaxon
Polar Surface Area	512.87 Å2	Chemaxon
Rotatable Bond Count	41	Chemaxon
Refractivity	431.13 m3·mol-1	Chemaxon
Polarizability	168.98 Å3	Chemaxon
Number of Rings	8	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.8352
Blood Brain Barrier	-	0.953
Caco-2 permeable	-	0.7556
P-glycoprotein substrate	Substrate	0.8461
P-glycoprotein inhibitor I	Non-inhibitor	0.6672
P-glycoprotein inhibitor II	Non-inhibitor	0.7791
Renal organic cation transporter	Non-inhibitor	0.8579
CYP450 2C9 substrate	Non-substrate	0.7299
CYP450 2D6 substrate	Non-substrate	0.8156
CYP450 3A4 substrate	Substrate	0.6482
CYP450 1A2 substrate	Non-inhibitor	0.8566
CYP450 2C9 inhibitor	Non-inhibitor	0.6493
CYP450 2D6 inhibitor	Non-inhibitor	0.8566
CYP450 2C19 inhibitor	Non-inhibitor	0.7291
CYP450 3A4 inhibitor	Non-inhibitor	0.5961
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.8478
Ames test	Non AMES toxic	0.652
Carcinogenicity	Non-carcinogens	0.7848
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.7005 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8534
hERG inhibition (predictor II)	Inhibitor	0.5235

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01pc-1311094000-f9acc076ac88d6a8faa9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03y0-1000169000-ac2fe33e15cdb7a73299
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03k9-3531295001-e561449a9dd3a344593e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-02ta-1000293000-8596ba6a17dcd371fd48
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-7904162000-3fe2009f5af6feb556ee
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-02tc-7412293002-1dc6e39e17f55cc1c6b1

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	3	N/A	N/A	A27289
Kd (nM)	1.58	N/A	N/A	A27289

Details

Binding Properties1. Gonadotropin-releasing hormone receptor

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. [Article]
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. [Article]
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. [Article]
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. [Article]

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Drug created at May 06, 2010 16:15 / Updated at February 20, 2024 23:54