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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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Nafarelin acetate
Brand names
  • Synarel
Brand name mixtures Not Available
Categories
  • Fertility Agents, Female
  • Gonadotropin-releasing hormones
  • Antiendometriotic agent
CAS number 76932-56-4
Weight Average: 1322.4713
Monoisotopic: 1321.635625827
Chemical Formula C66H83N17O13
InChI Key InChIKey=RWHUEXWOYVBUCI-UHFFFAOYSA-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)
Plain Text
IUPAC Name
N-(5-carbamimidamido-1-{2-[(carbamoylmethyl)carbamoyl]pyrrolidin-1-yl}-1-oxopentan-2-yl)-2-{2-[2-(3-hydroxy-2-{2-[3-(1H-imidazol-4-yl)-2-[(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)CC(NC(=O)C(CC1=CC2=C(C=CC=C2)C=C1)NC(=O)C(CC1=CC=C(O)C=C1)NC(=O)C(CO)NC(=O)C(CC1=CNC2=C1C=CC=C2)NC(=O)C(CC1=CNC=N1)NC(=O)C1CCC(=O)N1)C(=O)NC(CCCNC(N)=N)C(=O)N1CCCC1C(=O)NCC(N)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Polypeptides
  • Tryptamines and Derivatives
  • Gamma Lactams
Substructures
  • Polypeptides
  • Hydroxy Compounds
  • Naphthalenes
  • Indoles and Indole Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Pyrroles
  • Pyrrolidines
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Carboxylic Acids and Derivatives
  • Tryptamines and Derivatives
  • Carbamates and Derivatives
  • Alcohols and Polyols
  • Imidazoles
  • Phenethylamines
  • Heterocyclic compounds
  • Guanidines
  • Aromatic compounds
  • Carboxamidines
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Gamma Lactams
  • Lactams
  • Imines
  • Cyanamides
  • Phenyl Esters
  • Amphetamines
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.
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.
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
Pharmacoeconomics
Manufacturers
  • Gd searle llc
Packagers
Dosage forms
Form Route Strength
Aerosol, metered Nasal
Prices
Unit description Cost Unit
Synarel 2 mg/ml Solution 8ml Bottle 1150.16 USD bottle
Synarel 2 mg/ml nasal spray 138.24 USD ml
Synarel 2 mg/ml Solution 39.53 USD ml
Patents
Country Patent Number Approved Expires
Canada 1336401 1999-07-25 2012-07-25
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 1.66e-02 g/l ALOGPS
logP 1.21 ALOGPS
logP -4.63 ChemAxon Molconvert
logS -4.90 ALOGPS
pKa 10.98 ChemAxon Molconvert
hydrogen acceptor count 17 ChemAxon Molconvert
hydrogen donor count 17 ChemAxon Molconvert
polar surface area 472.13 ChemAxon Molconvert
rotatable bond count 33 ChemAxon Molconvert
refractivity 357.80 ChemAxon Molconvert
polarizability 137.29 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  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
  2. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. Pubmed
  3. Henzl MR: Gonadotropin-releasing hormone analogs: update on new findings. Am J Obstet Gynecol. 1992 Feb;166(2):757-61. Pubmed
  4. Burry KA: Nafarelin in the management of endometriosis: quality of life assessment. Am J Obstet Gynecol. 1992 Feb;166(2):735-9. Pubmed
  5. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. Pubmed
  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
  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
External Links
Resource Link
KEGG Compound C07613 Link_out
PubChem Compound 25077649 Link_out
PubChem Substance 46506496 Link_out
ChemSpider 10605761 Link_out
Therapeutic Targets Database DAP001051 Link_out
PharmGKB PA450574 Link_out
Drug Product Database 2188783 Link_out
RxList http://www.rxlist.com/cgi/generic2/nafarelin.htm Link_out
Drugs.com http://www.drugs.com/cdi/nafarelin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Nafarelin Link_out
ATC Codes
  • H01CA02
AHFS Codes
  • 68:18.00
PDB Entries Not Available
FDA label show (199.8 KB)
MSDS show (55.5 KB)
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. Gonadotropin-releasing hormone receptor

Pharmacological action: yes
Actions: agonist

Receptor for gonadotropin releasing hormone (GnRH) that mediate the action of GnRH to stimulate the secretion of the gonadotropic hormones (LH and FSH). This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act a an inhibitor of GnRH-R signaling

Organism class: human
UniProt ID: P30968 Link_out
Gene: GNRHR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Barbieri RL: Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990 Feb;162(2):581-5. Pubmed
  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
  3. Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann N Y Acad Sci. 2003 Nov;997:229-39. Pubmed
  4. Batzer FR: GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006 Nov-Dec;13(6):539-45. Pubmed
  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
  6. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. Pubmed
  7. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. Pubmed
  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
  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
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Gonadotropin-releasing hormone II receptor

Pharmacological action: yes
Actions: agonist

Receptor for gonadotropin releasing hormone II (GnRH II). This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system (Potential)

Organism class: human
UniProt ID: Q96P88 Link_out
Gene: GNRHR2 Link_out
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  3. Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann N Y Acad Sci. 2003 Nov;997:229-39. Pubmed
  4. Barbieri RL: Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990 Feb;162(2):581-5. Pubmed
  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
  6. Batzer FR: GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006 Nov-Dec;13(6):539-45. Pubmed
  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
  8. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. Pubmed
  9. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. Pubmed
  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
  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
  12. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:41

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.