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Histrelin

Synopsis, Chemistry

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Also known as: 76712-82-8, Histrelin acetate, Histrelinum, Orf 17070, Rwj 17070, Histrelina

Molecular Formula

C₆₆H₈₆N₁₈O₁₂

Molecular Weight

1323.5 g/mol

InChI Key

HHXHVIJIIXKSOE-QILQGKCVSA-N

FDA UNII

H50H3S3W74

Histrelin is a long-acting, synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH) with potential anti-tumor activity. Upon administration, histrelin binds to and activates GnRH receptors; prolonged administration results in pituitary GnRH receptor desensitization and inhibition of follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion, leading to a significant decline in testosterone production in males and may inhibit androgen receptor-positive tumor progression; in females, prolonged administration results in decreased estradiol production.

Histrelin is a Gonadotropin Releasing Hormone Receptor Agonist. The mechanism of action of histrelin is as a Gonadotropin Releasing Hormone Receptor Agonist.

1 2D Structure

Histrelin

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-3-(1-benzylimidazol-4-yl)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide

2.1.2 InChI

InChI=1S/C66H86N18O12/c1-4-70-64(95)55-17-11-25-84(55)65(96)48(16-10-24-71-66(67)68)76-58(89)49(26-38(2)3)77-62(93)53(30-43-34-83(37-74-43)33-40-12-6-5-7-13-40)81-59(90)50(27-39-18-20-44(86)21-19-39)78-63(94)54(35-85)82-60(91)51(28-41-31-72-46-15-9-8-14-45(41)46)79-61(92)52(29-42-32-69-36-73-42)80-57(88)47-22-23-56(87)75-47/h5-9,12-15,18-21,31-32,34,36-38,47-55,72,85-86H,4,10-11,16-17,22-30,33,35H2,1-3H3,(H,69,73)(H,70,95)(H,75,87)(H,76,89)(H,77,93)(H,78,94)(H,79,92)(H,80,88)(H,81,90)(H,82,91)(H4,67,68,71)/t47-,48-,49-,50-,51-,52-,53+,54-,55-/m0/s1

2.1.3 InChI Key

HHXHVIJIIXKSOE-QILQGKCVSA-N

2.1.4 Canonical SMILES

CCNC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(CC2=CN(C=N2)CC3=CC=CC=C3)NC(=O)C(CC4=CC=C(C=C4)O)NC(=O)C(CO)NC(=O)C(CC5=CNC6=CC=CC=C65)NC(=O)C(CC7=CN=CN7)NC(=O)C8CCC(=O)N8

2.1.5 Isomeric SMILES

CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2=CN(C=N2)CC3=CC=CC=C3)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC5=CNC6=CC=CC=C65)NC(=O)[C@H](CC7=CN=CN7)NC(=O)[C@@H]8CCC(=O)N8

2.2 Other Identifiers

2.2.1 UNII

H50H3S3W74

2.3 Synonyms

2.3.1 MeSH Synonyms

1. ((im Bzl)-d-his(6), Pro(9)-net)lhrh

2. 6-his(imbzl)-9-n-et-pronh2-10-des-glynh2-lhrh

3. Gnrh, His(imbzl)(6)-n-et-pronh2(9)-

4. Ibhpe-lhrh

5. Imbzl-his(6), Pro(9)-net-gnrh

6. Lhrh, His(imbzl)(6)-n-et-pronh2(9)-

7. Lhrh, Histidyl(imbzl)(6)-n-ethylprolinamide(9)-des-glycinamide(10)-

8. Supprelin

2.3.2 Depositor-Supplied Synonyms

1. 76712-82-8

2. Histrelin Acetate

3. Histrelinum

4. Orf 17070

5. Rwj 17070

6. Histrelina

7. Histreline

8. Vantas

9. Orf-17070

10. Chebi:5739

11. H50h3s3w74

12. Rwj-17070

13. Orf 17070rwj 17070

14. Vantaas

15. Vantas (tn)

16. Luteinizing Hormone-releasing Factor (pig), 6-(1-(phenylmethyl)-d-histidine)-9-(n-ethyl-l-prolinamide)-10-deglycinamide-

17. Histreline [french]

18. Histrelinum [latin]

19. Histrelina [spanish]

20. [(im-bzl)-d-his(6),pro(9)-net]-gonadotropin Releasing Hormone

21. Histrelin [usan:inn]

22. 1-9-luteinizing Hormone-releasing Factor (swine),6-[1-(phenylmethyl)-d-histidine]-9-(n-ethyl-l-prolinamide)-

23. 5-oxo-l-prolyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-1-benzyl-d-histidyl-l-leucyl-l-arginyl-n-ethyl-l-prolinamide

24. 5-oxo-l-prolyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-n(tau)-benzyl-d-histidyl-l-leucyl-l-arginyl-n-ethyl-l-prolinamide

25. L-pyroglutamyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-d-n(im)-benzyl-histidyl-l-leucyl-l-arginyl-l-proline Ethylamide

26. 220810-26-4

27. Brn 4290557

28. Unii-h50h3s3w74

29. Hsdb 7657

30. ((imbl)-d-his(sub 6),pro(sub 9)-net)lhrh

31. Histrelin [inn]

32. Histrelin [mi]

33. Histrelin (usan/inn)

34. Histrelin [hsdb]

35. Histrelin [usan]

36. Supprelin Lasupprelin La

37. Histrelin [vandf]

38. Histrelin [mart.]

39. Histrelin [who-dd]

40. Schembl17881

41. 5-oxo-l-prolyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-n(sup Tau)-benzyl-d-histidyl-l-leucyl-l-arginyl-n-ethyl-l-prolinamide

42. Gtpl3884

43. Chembl1201255

44. Schembl19409305

45. Schembl19712198

46. Schembl22288995

47. Dtxsid50227543

48. Hy-p0056

49. Ncgc00181758-01

50. Luteinizing Hormone-releasing Factor, 6-(1-(phenylmethyl)-d-histidine)-9-(n-ethyl-l-prolinamide)-10-deglycinamide-

51. Des-gly10,(d-his(bzl)6)-lh-rh*ethylamide

52. Cs-0015085

53. (des-gly10,d-his(bzl)6,pro-nhet9)-lhrh

54. D02369

55. 712h828

56. Q5871149

57. 5-oxo-l-prolyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-nt-benzyl-d-histidyl-l-leucyl-l-arginyl-n-ethyl-l-prolinamide

58. L-prolinamide, 5-oxo-l-prolyl-l-histidyl-l-tryptophyl-l-seryl-l-tyrosyl-1-(phenylmethyl)-d-histidyl-l-leucyl-l-arginyl-n-ethyl-

2.4 Create Date

2008-12-10

3 Chemical and Physical Properties

Molecular Formula	C₆₆H₈₆N₁₈O₁₂
Molecular Weight	1323.5 g/mol
XLogP3	0.7
Hydrogen Bond Donor Count	15
Hydrogen Bond Acceptor Count	15
Rotatable Bond Count	34
Exact Mass	1322.66726025 g/mol
Monoisotopic Mass	1322.66726025 g/mol
Topological Polar Surface Area	449 Å²
Heavy Atom Count	96
Formal Charge	0
Complexity	2660
Isotope Atom Count	0
Defined Atom Stereocenter Count	9
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Information

1 of 4
Drug Name	Supprelin la
PubMed Health	Histrelin (Implantation)
Drug Classes	Endocrine-Metabolic Agent
Active Ingredient	Histrelin acetate
Dosage Form	Implant
Route	Subcutaneous
Strength	50mg
Market Status	Prescription
Company	Endo Pharm

2 of 4
Drug Name	Vantas
PubMed Health	Histrelin (Implantation)
Drug Classes	Endocrine-Metabolic Agent
Active Ingredient	Histrelin acetate
Dosage Form	Implant
Route	Subcutaneous
Strength	50mg
Market Status	Prescription
Company	Endo Pharm

3 of 4
Drug Name	Supprelin la
PubMed Health	Histrelin (Implantation)
Drug Classes	Endocrine-Metabolic Agent
Active Ingredient	Histrelin acetate
Dosage Form	Implant
Route	Subcutaneous
Strength	50mg
Market Status	Prescription
Company	Endo Pharm

4 of 4
Drug Name	Vantas
PubMed Health	Histrelin (Implantation)
Drug Classes	Endocrine-Metabolic Agent
Active Ingredient	Histrelin acetate
Dosage Form	Implant
Route	Subcutaneous
Strength	50mg
Market Status	Prescription
Company	Endo Pharm

4.2 Therapeutic Uses

Gonadotropin-Releasing Hormone agonist

National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)

/Histrelin/ is indicated in the palliative treatment of advanced prostate cancer. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for Vantas (Histrelin acetate) (Implant) (May 2008). Available from, as of November 9, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7362

/Histrelin/ is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of children with central precocious puberty (CPP). /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for Supprelin LA (Histrelin acetate) (Implant) (August 2008). Available from, as of November 9, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8125

4.3 Drug Warning

/Histrelin is contraindicated in patients with/ known hypersensitivity to histrelin or any ingredient in the formulation, other gonadotropin-releasing hormone (GnRH) agonists, or GnRH.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1082

Like other GnRH agonists, histrelin causes a transient increase in serum testosterone concentrations during the first week of treatment. Worsening of signs and/or symptoms of prostate cancer and/or development of new manifestations (e.g., bone pain, neuropathy, hematuria, ureteral or bladder outlet obstruction) may occur during the first few weeks of therapy.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1082

Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1082

Anaphylactic reactions have been reported with synthetic gonadotropin-releasing hormone (GnRH) or GnRH agonists.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1082

For more Drug Warnings (Complete) data for HISTRELIN (16 total), please visit the HSDB record page.

5 Pharmacology and Biochemistry

5.1 FDA Pharmacological Classification

5.1.1 Active Moiety

HISTRELIN

5.1.2 FDA UNII

H50H3S3W74

5.1.3 Pharmacological Classes

Gonadotropin Releasing Hormone Receptor Agonists [MoA]; Gonadotropin Releasing Hormone Receptor Agonist [EPC]

5.2 ATC Code

L - Antineoplastic and immunomodulating agents

L02 - Endocrine therapy

L02A - Hormones and related agents

L02AE - Gonadotropin releasing hormone analogues

L02AE05 - Histrelin

5.3 Absorption, Distribution and Excretion

Histrelin acetate is not active when given orally.

Following subcutaneous insertion of a histrelin acetate implant in patients with advanced prostate cancer, peak serum concentrations of histrelin occurred at a median of 12 hours; the drug is delivered continuously at a rate of 50-60 ug daily over 12 months.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1083

Following subcutaneous insertion of one Vantas (histrelin implant) 50 mg implant in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 +/- 0.375 ng/mL (mean +/- SD) occurred at a median of 12 hours.

The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 +/- 7.71 ug/day over the 52 week dosing period.

For more Absorption, Distribution and Excretion (Complete) data for HISTRELIN (8 total), please visit the HSDB record page.

5.4 Metabolism/Metabolites

An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites.

5.5 Biological Half-Life

The mean terminal half-life of the drug following subcutaneous injection of a single 500-ug dose was approximately 3.92 hours in healthy men.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1083

5.6 Mechanism of Action

Histrelin acetate is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin).

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1083

Histrelin is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. After initial administration of histrelin, there is a transient surge in circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadal steroids (testosterone and dihydrotestosterone in males). Following chronic and continuous administration of histrelin (generally, 2-4 weeks after initiation of therapy), a sustained decrease in LH and FSH secretion and a marked reduction in serum testosterone concentrations are observed. Reductions in serum testosterone concentrations in males receiving histrelin are comparable to those achieved after surgical castration (i.e., less than 50 ng/dL).

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1083

Histrelin acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn, causes a reduction in testicular steroidogenesis. In humans, administration of histrelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous administration of histrelin acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within 2 to 4 weeks after initiation of treatment.

The possible direct effect of gonadotropin-releasing hormone (GnRH) and a potent GnRH agonist [( imBzl )-D- His6 -Pro9-NEt]-GnRH on basal and human chorionic gonadotropin (hCG)-stimulated progesterone, androstenedione, and estradiol production by cultured human luteal cells was examined. Luteal cells from the early or midluteal phase of the menstrual cycle responded to hCG stimulation with two to fivefold increases in steroid production in both short-term (4 hours) and long-term (up to 144 hours) culture in chemically defined medium without serum. After 48 hours in this system, levels of androstenedione and estradiol were very low, and progesterone was the predominant steroid produced. The addition of GnRH or a potent GnRH agonist to the medium had no effect on either basal or hCG-stimulated steroid secretion. When luteal cells were cultured longer (for up to 10 days) in the presence of serum, GnRH agonist caused no significant alteration of either basal or hCG-stimulated progesterone production. Collectively, these results support the conclusion that GnRH and its potent agonist do not act directly on human corpora luteal cells to modulate steroidogenesis.

PMID:6373386 Casper RF et al; Fertil Steril 42 (1): 39-43 (1984)