Nafarelin

Identification

Name
Nafarelin
Accession Number
DB00666
Description

Nafarelin is a potent synthetic agonist of gonadotropin-releasing hormone with 3-(2-naphthyl)-D-alanine substitution at residue 6. Nafarelin has been used in the treatments of central precocious puberty and endometriosis.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 1322.496
Monoisotopic: 1321.635625801
Chemical Formula
C66H83N17O13
Synonyms
  • Nafarelin
  • Nafarelina
  • Nafaréline
  • Nafarelinum
External IDs
  • RS-94991-298

Pharmacology

Indication

For treatment of central precocious puberty (true precocious puberty, GnRH-dependent precocious precocity, complete isosexual precocity) in children of both sexes and for the treatment of endometriosis.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Nafarelin is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. After nafarelin therapy is discontinued, pituitary and ovarian function normalize and estradiol serum concentrations increase to pretreatment levels. Recurrences of endometriosis are frequent after cessation of any hormonal therapy, or surgery that leaves the ovaries and/or uterus intact.

Mechanism of action

Like GnRH, initial or intermittent administration of nafarelin stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor, leading to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. This causes a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes. Like normal endometrium, endometriotic implants contain estrogen receptors. Estrogen stimulates the growth of endometrium. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants. However, nafarelin does not abolish the underlying pathophysiology of endometriosis. In children with central precocious puberty receiving nafarelin, serum LH, testosterone, and estradiol concentrations return to prepubertal levels. This results in the supression of secondary sexual characteristics and decrased rate of linear growth and skeletal maturation. Following disconinuation of nafarelin, the effects of the drug is reversed, meaning FSH and LH concentrations usually return to pretreatment levels.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
agonist
Humans
APutative gonadotropin-releasing hormone II receptor
agonist
Humans
Absorption

Rapidly absorbed into the systemic circulation after intranasal administration. Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). Not absorbed after oral administration.

Volume of distribution
Not Available
Protein binding

Approximately 80%.

Metabolism

Enzymatic hydrolysis.

Route of elimination
Not Available
Half-life

3 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs.

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
AcipimoxThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Acipimox.
Alendronic acidThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Alendronic acid is combined with Nafarelin.
AmiodaroneThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Amiodarone.
Amphotericin BThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Amphotericin B.
AtorvastatinThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Atorvastatin.
BaclofenThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Baclofen is combined with Nafarelin.
BetamethasoneThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Betamethasone is combined with Nafarelin.
BezafibrateThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Bezafibrate.
BumetanideThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Bumetanide.
Capromab pendetideNafarelin may decrease effectiveness of Capromab pendetide as a diagnostic agent.
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

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid excessive or chronic alcohol consumption. Ingesting alcohol in excess may increase the risk of bone thinning associated with taking nafarelin.

Products

Product Ingredients
IngredientUNIICASInChI Key
Nafarelin acetate8ENZ0QJW4H86220-42-0FSBTYDWUUWLHBD-UDXTWCDOSA-N
International/Other Brands
Nafarelil (Fuji Yakuhin) / Nasanyl (Pfizer) / Synarela (Pfizer) / Synrelina (Pfizer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SynarelAerosol, metered200 mcgNasalPfizer Canada Ulc1996-11-25Not applicableCanada flag
SynarelSpray, metered2 mg/1mLNasalG.D. Searle LLC Division of Pfizer Inc1990-02-13Not applicableUS flag
Synarel Nas Sol 2mg/mlLiquidNasalSyntex Inc.1991-12-311996-09-30Canada flag
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
H01CA02 — Nafarelin
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 / Tyrosine and derivatives / Phenylalanine and derivatives / Histidine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Alpha amino acid amides / Serine and derivatives / Tryptamines and derivatives
show 24 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / 2-pyrrolidone / 3-alkylindole / Alcohol / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amphetamine or derivatives / Aromatic heteropolycyclic compound / Azacycle
show 49 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
1X0094V6JV
CAS number
76932-56-4
InChI Key
RWHUEXWOYVBUCI-ITQXDASVSA-N
InChI
InChI=1S/C66H83N17O13/c1-36(2)25-48(58(89)76-47(13-7-23-71-66(68)69)65(96)83-24-8-14-54(83)64(95)73-33-55(67)86)77-60(91)50(28-38-15-18-39-9-3-4-10-40(39)26-38)78-59(90)49(27-37-16-19-43(85)20-17-37)79-63(94)53(34-84)82-61(92)51(29-41-31-72-45-12-6-5-11-44(41)45)80-62(93)52(30-42-32-70-35-74-42)81-57(88)46-21-22-56(87)75-46/h3-6,9-12,15-20,26,31-32,35-36,46-54,72,84-85H,7-8,13-14,21-25,27-30,33-34H2,1-2H3,(H2,67,86)(H,70,74)(H,73,95)(H,75,87)(H,76,89)(H,77,91)(H,78,90)(H,79,94)(H,80,93)(H,81,88)(H,82,92)(H4,68,69,71)/t46-,47-,48-,49-,50+,51-,52-,53-,54-/m0/s1
IUPAC Name
(2S)-N-[(2S)-5-carbamimidamido-1-[(2S)-2-[(carbamoylmethyl)carbamoyl]pyrrolidin-1-yl]-1-oxopentan-2-yl]-2-[(2R)-2-[(2S)-2-[(2S)-3-hydroxy-2-[(2S)-2-[(2S)-3-(1H-imidazol-4-yl)-2-{[(2S)-5-oxopyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-3-yl)propanamido]propanamido]-3-(4-hydroxyphenyl)propanamido]-3-(naphthalen-2-yl)propanamido]-4-methylpentanamide
SMILES
CC(C)C[[email protected]](NC(=O)[[email protected]@H](CC1=CC2=C(C=CC=C2)C=C1)NC(=O)[[email protected]](CC1=CC=C(O)C=C1)NC(=O)[[email protected]](CO)NC(=O)[[email protected]](CC1=CNC2=CC=CC=C12)NC(=O)[[email protected]](CC1=CNC=N1)NC(=O)[[email protected]@H]1CCC(=O)N1)C(=O)N[[email protected]@H](CCCNC(N)=N)C(=O)N1CCC[[email protected]]1C(=O)NCC(N)=O

References

General References
  1. Hugues JN, Cedrin Durnerin IC: Revisiting gonadotrophin-releasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum Reprod Update. 1998 Jan-Feb;4(1):83-101. [PubMed:9622415]
  2. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. [PubMed:7996307]
  3. Henzl MR: Gonadotropin-releasing hormone analogs: update on new findings. Am J Obstet Gynecol. 1992 Feb;166(2):757-61. [PubMed:1531579]
  4. Burry KA: Nafarelin in the management of endometriosis: quality of life assessment. Am J Obstet Gynecol. 1992 Feb;166(2):735-9. [PubMed:1531576]
  5. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. [PubMed:1830521]
  6. Chrisp P, Goa KL: Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. 1990 Apr;39(4):523-51. [PubMed:2140979]
  7. Letassy NA, Thompson DF, Britton ML, Suda RR Sr: Nafarelin acetate: a gonadotropin-releasing hormone agonist for the treatment of endometriosis. DICP. 1990 Dec;24(12):1204-9. [PubMed:2151003]
KEGG Compound
C07613
PubChem Compound
25077405
PubChem Substance
46506496
ChemSpider
10482014
BindingDB
84707
RxNav
28656
ChEMBL
CHEMBL1201309
Therapeutic Targets Database
DAP001051
PharmGKB
PA164754805
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Nafarelin
AHFS Codes
  • 68:18.00 — Gonadotropins and Antigonadotropins
FDA label
Download (200 KB)
MSDS
Download (55.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentInfertility1
1, 2CompletedTreatmentEndometriosis / Pelvic Pain1
Not AvailableCompletedOtherInfertility1

Pharmacoeconomics

Manufacturers
  • Gd searle llc
Packagers
  • GD Searle LLC
  • Pfizer Inc.
  • Pharmacia Inc.
Dosage Forms
FormRouteStrength
Aerosol, meteredNasal200 mcg
Spray, meteredNasal2 mg/1mL
LiquidNasal
Prices
Unit descriptionCostUnit
Synarel 2 mg/ml Solution 8ml Bottle1150.16USD bottle
Synarel 2 mg/ml nasal spray138.24USD ml
Synarel 2 mg/ml Solution39.53USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA1336401No1999-07-252012-07-25Canada flag
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 Solubility0.0166 mg/mLALOGPS
logP1.21ALOGPS
logP-2.7ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)9.49ChemAxon
pKa (Strongest Basic)11.92ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count17ChemAxon
Polar Surface Area472.13 Å2ChemAxon
Rotatable Bond Count33ChemAxon
Refractivity357.8 m3·mol-1ChemAxon
Polarizability135.67 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9695
Blood Brain Barrier-0.9781
Caco-2 permeable-0.8941
P-glycoprotein substrateSubstrate0.8607
P-glycoprotein inhibitor INon-inhibitor0.8452
P-glycoprotein inhibitor IINon-inhibitor0.7859
Renal organic cation transporterNon-inhibitor0.6797
CYP450 2C9 substrateNon-substrate0.769
CYP450 2D6 substrateNon-substrate0.7647
CYP450 3A4 substrateSubstrate0.5996
CYP450 1A2 substrateNon-inhibitor0.842
CYP450 2C9 inhibitorNon-inhibitor0.8493
CYP450 2D6 inhibitorNon-inhibitor0.9054
CYP450 2C19 inhibitorNon-inhibitor0.8136
CYP450 3A4 inhibitorNon-inhibitor0.7529
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9411
Ames testNon AMES toxic0.6992
CarcinogenicityNon-carcinogens0.7961
BiodegradationNot ready biodegradable0.9933
Rat acute toxicity2.6799 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9038
hERG inhibition (predictor II)Non-inhibitor0.5274
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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
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. Barbieri RL: Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990 Feb;162(2):581-5. [PubMed:2137975]
  2. Suh J, Lee E, Hwang S, Yoon S, Yoon BK, Bae D, Choi D: Dose of GnRH agonist (nafarelin acetate) affects intrafollicular PAPP-A expression in controlled ovarian hyperstimulation cycle. Eur J Obstet Gynecol Reprod Biol. 2004 Jan 15;112(1):65-8. [PubMed:14687742]
  3. Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann N Y Acad Sci. 2003 Nov;997:229-39. [PubMed:14644830]
  4. Batzer FR: GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006 Nov-Dec;13(6):539-45. [PubMed:17097577]
  5. Hugues JN, Cedrin Durnerin IC: Revisiting gonadotrophin-releasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum Reprod Update. 1998 Jan-Feb;4(1):83-101. [PubMed:9622415]
  6. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. [PubMed:7996307]
  7. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. [PubMed:1830521]
  8. Chrisp P, Goa KL: Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. 1990 Apr;39(4):523-51. [PubMed:2140979]
  9. Letassy NA, Thompson DF, Britton ML, Suda RR Sr: Nafarelin acetate: a gonadotropin-releasing hormone agonist for the treatment of endometriosis. DICP. 1990 Dec;24(12):1204-9. [PubMed:2151003]
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Gonadotropin-releasing hormone receptor activity
Specific Function
Putative receptor for gonadotropin releasing hormone II (GnRH II) which is most probably non-functional.
Gene Name
GNRHR2
Uniprot ID
Q96P88
Uniprot Name
Putative gonadotropin-releasing hormone II receptor
Molecular Weight
32536.935 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann N Y Acad Sci. 2003 Nov;997:229-39. [PubMed:14644830]
  4. Barbieri RL: Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990 Feb;162(2):581-5. [PubMed:2137975]
  5. Suh J, Lee E, Hwang S, Yoon S, Yoon BK, Bae D, Choi D: Dose of GnRH agonist (nafarelin acetate) affects intrafollicular PAPP-A expression in controlled ovarian hyperstimulation cycle. Eur J Obstet Gynecol Reprod Biol. 2004 Jan 15;112(1):65-8. [PubMed:14687742]
  6. Batzer FR: GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006 Nov-Dec;13(6):539-45. [PubMed:17097577]
  7. Hugues JN, Cedrin Durnerin IC: Revisiting gonadotrophin-releasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum Reprod Update. 1998 Jan-Feb;4(1):83-101. [PubMed:9622415]
  8. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. [PubMed:7996307]
  9. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. [PubMed:1830521]
  10. Chrisp P, Goa KL: Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. 1990 Apr;39(4):523-51. [PubMed:2140979]
  11. Letassy NA, Thompson DF, Britton ML, Suda RR Sr: Nafarelin acetate: a gonadotropin-releasing hormone agonist for the treatment of endometriosis. DICP. 1990 Dec;24(12):1204-9. [PubMed:2151003]

Drug created on June 13, 2005 07:24 / Updated on September 22, 2020 02:11

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