Identification

Name
Nafarelin
Accession Number
DB00666  (APRD01129)
Type
Small Molecule
Groups
Approved
Description

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. [PubChem]

Structure
Thumb
Synonyms
  • Nafarelin
  • Nafarelina
  • Nafaréline
  • Nafarelinum
External IDs
RS-94991-298
Product Ingredients
IngredientUNIICASInChI Key
Nafarelin acetate hydrate8ENZ0QJW4H86220-42-0FSBTYDWUUWLHBD-UDXTWCDOSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SynarelAerosol, metered2 mgNasalPfizer1996-11-25Not applicableCanada
SynarelSpray, metered2 mg/1mLNasalG.D. Searle LLC Division of Pfizer Inc1990-02-13Not applicableUs
Synarel Nas Sol 2mg/mlLiquid2 mgNasalSyntex Inc.1991-12-311996-09-30Canada
International/Other Brands
Nafarelil (Fuji Yakuhin) / Nasanyl (Pfizer) / Synarela (Pfizer) / Synrelina (Pfizer)
Categories
UNII
1X0094V6JV
CAS number
76932-56-4
Weight
Average: 1322.496
Monoisotopic: 1321.635625801
Chemical Formula
C66H83N17O13
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)-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[C@H](NC(=O)[C@@H](CC1=CC2=CC=CC=C2C=C1)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CNC2=CC=CC=C12)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O

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
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
Human
APutative gonadotropin-releasing hormone II receptor
agonist
Human
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
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
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.
Aluminium clofibrateThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Nafarelin is combined with Aluminium clofibrate.
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.
Food Interactions
Not Available

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]
External Links
KEGG Compound
C07613
PubChem Compound
25077405
PubChem Substance
46506496
ChemSpider
10482014
BindingDB
84707
ChEMBL
CHEMBL1201309
Therapeutic Targets Database
DAP001051
PharmGKB
PA164754805
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Nafarelin
ATC Codes
H01CA02 — Nafarelin
AHFS Codes
  • 68:18.00 — Gonadotropins
FDA label
Download (200 KB)
MSDS
Download (55.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentEndometriosis / Pelvic Pain1
Not AvailableCompletedOtherInfertilities1

Pharmacoeconomics

Manufacturers
  • Gd searle llc
Packagers
  • GD Searle LLC
  • Pfizer Inc.
  • Pharmacia Inc.
Dosage forms
FormRouteStrength
Aerosol, meteredNasal2 mg
Spray, meteredNasal2 mg/1mL
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)
CA1336401No1999-07-252012-07-25Canada

Properties

State
Solid
Experimental Properties
Not 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 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

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 / 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
Polypeptide / Alpha peptide / Tyrosine or derivatives / Phenylalanine or derivatives / Histidine or derivatives / Leucine or derivatives / N-acyl-alpha amino acid or derivatives / Proline or derivatives / Alpha-amino acid amide / Triptan
show 49 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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...
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
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
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 November 21, 2018 07:14