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Identification
NameNafarelin
Accession NumberDB00666  (APRD01129)
TypeSmall Molecule
GroupsApproved
DescriptionA 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. [PubChem]
Structure
Thumb
Synonyms
Nafarelin
Nafarelina
Nafaréline
Nafarelinum
External Identifiers
  • RS-94991-298
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SynarelSpray, metered2 mg/mLNasalG.D. Searle LLC Division of Pfizer Inc1990-02-13Not applicableUs
SynarelAerosol, metered2 mgNasalPfizer Canada Inc1996-11-25Not applicableCanada
Synarel Nas Sol 2mg/mlLiquid2 mgNasalSyntex Inc.1991-12-311996-09-30Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
NafarelilFuji Yakuhin
NasanylPfizer
SynarelaPfizer
SynrelinaPfizer
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Nafarelin acetate hydrate
86220-42-0
Thumb
  • InChI Key: FSBTYDWUUWLHBD-UDXTWCDOSA-N
  • Monoisotopic Mass: 1399.667319854
  • Average Mass: 1400.563
DBSALT000324
Categories
UNII1X0094V6JV
CAS number76932-56-4
WeightAverage: 1322.496
Monoisotopic: 1321.635625801
Chemical FormulaC66H83N17O13
InChI KeyRWHUEXWOYVBUCI-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)-1-[(2S)-2-[(carbamoylmethyl)carbamoyl]pyrrolidin-1-yl]-5-[(diaminomethylidene)amino]-1-oxopentan-2-yl]-2-[(2R)-2-[(2S)-2-[(2S)-3-hydroxy-2-[(2S)-2-[(2S)-3-(1H-imidazol-5-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)[C@@H](CC1=CC2=CC=CC=C2C=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=CN=CN1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[[email protected]]1C(=O)NCC(N)=O
Pharmacology
IndicationFor 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.
Structured Indications
PharmacodynamicsNafarelin 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 actionLike 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.
TargetKindPharmacological actionActionsOrganismUniProt ID
Gonadotropin-releasing hormone receptorProteinyes
agonist
HumanP30968 details
Putative gonadotropin-releasing hormone II receptorProteinyes
agonist
HumanQ96P88 details
Related Articles
AbsorptionRapidly 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 distributionNot Available
Protein bindingApproximately 80%.
Metabolism

Enzymatic hydrolysis.

Route of eliminationNot Available
Half life3 hours
ClearanceNot Available
ToxicityIn 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
Choline C 11The therapeutic efficacy of Choline C 11 can be decreased when used in combination with Nafarelin.Approved
Corifollitropin AlfaThe therapeutic efficacy of Corifollitropin Alfa can be increased when used in combination with Nafarelin.Approved
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
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 ]
External Links
ATC CodesH01CA02
AHFS Codes
  • 68:18.00
PDB EntriesNot Available
FDA labelDownload (200 KB)
MSDSDownload (55.5 KB)
ADMET
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 )
Pharmacoeconomics
Manufacturers
  • Gd searle llc
Packagers
Dosage forms
FormRouteStrength
Aerosol, meteredNasal2 mg
Spray, meteredNasal2 mg/mL
LiquidNasal2 mg
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)
CA1336401 No1999-07-252012-07-25Canada
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0144 mg/mLALOGPS
logP1.27ALOGPS
logP-3.1ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)9.47ChemAxon
pKa (Strongest Basic)11.16ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count16ChemAxon
Polar Surface Area474.63 Å2ChemAxon
Rotatable Bond Count33ChemAxon
Refractivity348.07 m3·mol-1ChemAxon
Polarizability137.6 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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
  • Tyrosine or derivatives
  • Phenylalanine or derivatives
  • Histidine or derivatives
  • Leucine or derivatives
  • Proline or derivatives
  • N-acyl-alpha amino acid or derivatives
  • Triptan
  • Alpha-amino acid amide
  • Serine or derivatives
  • Amphetamine or derivatives
  • 3-alkylindole
  • Alpha-amino acid or derivatives
  • Naphthalene
  • N-substituted-alpha-amino acid
  • Indole
  • Indole or derivatives
  • N-acylpyrrolidine
  • Pyrrolidine carboxylic acid or derivatives
  • Pyrrolidine-2-carboxamide
  • 1-hydroxy-2-unsubstituted benzenoid
  • Phenol
  • Benzenoid
  • Substituted pyrrole
  • 2-pyrrolidone
  • Pyrrolidone
  • Monocyclic benzene moiety
  • Fatty amide
  • N-acyl-amine
  • Fatty acyl
  • Tertiary carboxylic acid amide
  • Azole
  • Pyrrolidine
  • Pyrrole
  • Imidazole
  • Heteroaromatic compound
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Primary carboxylic acid amide
  • Guanidine
  • Lactam
  • Organoheterocyclic compound
  • Carboximidamide
  • Carboxylic acid derivative
  • Propargyl-type 1,3-dipolar organic compound
  • Organic 1,3-dipolar compound
  • Azacycle
  • Hydrocarbon derivative
  • Primary alcohol
  • Organic oxygen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Organic oxide
  • Organooxygen compound
  • Alcohol
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
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 (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. 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
Human
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
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 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23