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Examorelin

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Examorelin
Clinical data
Other namesL-Histidyl-2-methyl-D-tryptophyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide
Routes of
administration		Intravenous,subcutaneous,intranasal,oral[1]
ATC code
  • None
Pharmacokinetic data
Eliminationhalf-life~55 minutes[2]
Identifiers
  • (2S)-6-amino-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(2-methyl-1H-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC47H58N12O6
Molar mass887.059 g·mol−1
3D model (JSmol)
  • CC1=C(C2=CC=CC=C2N1)C[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@H](CC5=CC=CC=C5)C(=O)N[C@@H](CCCCN)C(=O)N)NC(=O)[C@H](CC6=CNC=N6)N
  • InChI=1S/C47H58N12O6/c1-27-34(33-15-7-9-17-37(33)54-27)23-41(58-44(62)35(49)22-31-25-51-26-53-31)45(63)55-28(2)43(61)57-40(21-30-24-52-36-16-8-6-14-32(30)36)47(65)59-39(20-29-12-4-3-5-13-29)46(64)56-38(42(50)60)18-10-11-19-48/h3-9,12-17,24-26,28,35,38-41,52,54H,10-11,18-23,48-49H2,1-2H3,(H2,50,60)(H,51,53)(H,55,63)(H,56,64)(H,57,61)(H,58,62)(H,59,65)/t28-,35-,38-,39+,40-,41+/m0/s1
  • Key:RVWNMGKSNGWLOL-GIIHNPQRSA-N

Examorelin (INN) (developmental code namesEP-23905,MF-6003), also known ashexarelin, is apotent,synthetic,peptidic,orally-active,centrally-penetrant, and highly selectiveagonist of theghrelin/growth hormone secretagogue receptor (GHSR) and agrowth hormone secretagogue which was developed byMediolanum Farmaceutici.[3][4][5][6][7] It is ahexapeptide with theamino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived fromGHRP-6. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at theghrelin receptor.[5][6]

Examorelin substantially and dose-dependently increasesplasma levels ofgrowth hormone (GH) in animals and humans.[2] In addition, similarly topralmorelin (GHRP-2) and GHRP-6, it slightly and dose-dependently stimulates the release ofprolactin,adrenocorticotropic hormone (ACTH), andcortisol in humans.[2][8] There are conflicting reports on the ability of examorelin to elevateinsulin-like growth factor 1 (IGF-1) andinsulin-like growth factor-binding protein 1 (IGFBP-1) levels in humans, with some studies finding no increase and others finding a slight yet statistically significant increase.[2][9][10][11] Examorelin does not affect plasma levels ofglucose,luteinizing hormone (LH),follicle-stimulating hormone (FSH), orthyroid-stimulating hormone (TSH) in humans.[2]

Examorelin releases more GH than doesgrowth hormone-releasing hormone (GHRH) in humans,[8][12] and produces synergistic effects on GH release in combination with GHRH, resulting in "massive" increases in plasma GH levels even with only low doses of examorelin.[13][14][15] Pre-administration of GH blunts the GH-releasing effect of examorelin, while, in contrast, fully abolishing the effect of GHRH.[14][16] Pre-treatment with IGF-1 also blunts the GH-elevating effect of examorelin.[17]Testosterone,testosterone enanthate, andethinylestradiol, though notoxandrolone, have been found to significantly potentiate the GH-releasing effects of examorelin in humans.[18][19] In accordance, likely due to increases insex steroid levels,puberty has also been found to significantly augment the GH-elevating actions of examorelin in humans.[20]

A partial and reversible tolerance to the GH-releasing effects of examorelin occurs in humans with long-term administration (50–75% decrease in efficacy over the course of weeks to months).[21][22]

Examorelin reachedphase IIclinical trials for the treatment ofgrowth hormone deficiency andcongestive heart failure but did not complete development and was never marketed.[6][23]

See also

[edit]

References

[edit]
  1. ^Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F (March 1994). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man".The Journal of Clinical Endocrinology and Metabolism.78 (3):693–698.doi:10.1210/jcem.78.3.8126144.PMID 8126144.
  2. ^abcdeImbimbo BP, Mant T, Edwards M, Amin D, Dalton N, Boutignon F, et al. (1994). "Growth hormone-releasing activity of hexarelin in humans. A dose-response study".European Journal of Clinical Pharmacology.46 (5):421–425.doi:10.1007/bf00191904.PMID 7957536.S2CID 19573322.
  3. ^Ganellin CR, Triggle DJ (21 November 1996).Dictionary of Pharmacological Agents. CRC Press. pp. 617–.ISBN 978-0-412-46630-4.
  4. ^Morton IK, Hall JM (6 December 2012).Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 117–.ISBN 978-94-011-4439-1.
  5. ^abMoulin A, Ryan J, Martinez J, Fehrentz JA (September 2007). "Recent developments in ghrelin receptor ligands".ChemMedChem.2 (9):1242–1259.doi:10.1002/cmdc.200700015.PMID 17520591.S2CID 24945528.
  6. ^abcWang Y, Tomlinson B (March 2009). "Tesamorelin, a human growth hormone releasing factor analogue".Expert Opinion on Investigational Drugs.18 (3):303–310.doi:10.1517/13543780802707658.PMID 19243281.S2CID 71177320.
  7. ^Carpino PA (2002). "Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists".Expert Opinion on Therapeutic Patents.12 (11):1599–1618.doi:10.1517/13543776.12.11.1599.S2CID 83645573.
  8. ^abArvat E, di Vito L, Maccagno B, Broglio F, Boghen MF, Deghenghi R, et al. (1997). "Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH".Peptides.18 (6):885–891.doi:10.1016/s0196-9781(97)00016-8.PMID 9285939.S2CID 25480336.
  9. ^Ghigo E, Arvat E, Gianotti L, Grottoli S, Rizzi G, Ceda GP, et al. (October 1996). "Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging".European Journal of Endocrinology.135 (4):407–412.doi:10.1530/eje.0.1350407.PMID 8921821.
  10. ^Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A (November 1995). "Intranasal administration of the GHRP hexarelin accelerates growth in short children".Clinical Endocrinology.43 (5):631–635.doi:10.1111/j.1365-2265.1995.tb02929.x.PMID 8548949.S2CID 30980163.
  11. ^Frenkel J, Silbergeld A, Deghenghi R, Laron Z (1995). "Short term effect of intranasal administration of hexarelin--a synthetic growth hormone-releasing peptide. Preliminary communication".Journal of Pediatric Endocrinology & Metabolism.8 (1):43–45.doi:10.1515/jpem.1995.8.1.43.PMID 7584696.S2CID 6791525.
  12. ^Maccario M, Arvat E, Procopio M, Gianotti L, Grottoli S, Imbimbo BP, et al. (January 1995). "Metabolic modulation of the growth hormone-releasing activity of hexarelin in man".Metabolism.44 (1):134–138.doi:10.1016/0026-0495(95)90300-3.PMID 7854159.
  13. ^Massoud AF, Hindmarsh PC, Brook CG (December 1996)."Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study".The Journal of Clinical Endocrinology and Metabolism.81 (12):4338–4341.doi:10.1210/jcem.81.12.8954038.PMID 8954038.
  14. ^abArvat E, Di Vito L, Gianotti L, Ramunni J, Boghen MF, Deghenghi R, et al. (January 1997). "Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man".Metabolism.46 (1):83–88.doi:10.1016/s0026-0495(97)90173-6.PMID 9005975.
  15. ^Arvat E, Gianotti L, Di Vito L, Imbimbo BP, Lenaerts V, Deghenghi R, et al. (January 1995). "Modulation of growth hormone-releasing activity of hexarelin in man".Neuroendocrinology.61 (1):51–56.doi:10.1159/000126827.PMID 7731498.
  16. ^Massoud AF, Hindmarsh PC, Brook CG (November 1995). "Hexarelin induced growth hormone release is influenced by exogenous growth hormone".Clinical Endocrinology.43 (5):617–621.doi:10.1111/j.1365-2265.1995.tb02927.x.PMID 8548947.S2CID 31571160.
  17. ^Owusu-Apenten R (23 June 2010)."Anabolic Dysfunction".Bioactive Peptides: Applications for Improving Nutrition and Health. CRC Press. pp. 292–.ISBN 978-1-4398-1363-8.
  18. ^Loche S, Colao A, Cappa M, Bellone J, Aimaretti G, Farello G, et al. (March 1997)."The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids".The Journal of Clinical Endocrinology and Metabolism.82 (3):861–864.doi:10.1210/jcem.82.3.3795.PMID 9062497.
  19. ^Loche S, Cambiaso P, Carta D, Setzu S, Imbimbo BP, Borrelli P, et al. (February 1995). "The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects".The Journal of Clinical Endocrinology and Metabolism.80 (2):674–678.doi:10.1210/jcem.80.2.7852535.PMID 7852535.
  20. ^Bellone J, Aimaretti G, Bartolotta E, Benso L, Imbimbo BP, Lenhaerts V, et al. (April 1995). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty".The Journal of Clinical Endocrinology and Metabolism.80 (4):1090–1094.doi:10.1210/jcem.80.4.7714074.PMID 7714074.
  21. ^Rahim A, O'Neill PA, Shalet SM (May 1998)."Growth hormone status during long-term hexarelin therapy".The Journal of Clinical Endocrinology and Metabolism.83 (5):1644–1649.doi:10.1210/jcem.83.5.4812.PMID 9589671.
  22. ^Ghigo E (1999).Growth Hormone Secretagogues: Basic Findings and Clinical Implications. Elsevier. pp. 178–.ISBN 978-0-444-82933-7.
  23. ^Suckling K (November 2006). "Discontinued drugs in 2005: cardiovascular drugs".Expert Opinion on Investigational Drugs.15 (11):1299–1308.doi:10.1517/13543784.15.11.1299.PMID 17040192.S2CID 21632578.
GH
(somatotropin)
GHIH
(somatostatin)
GHRH
(somatocrinin)
GHS
(ghrelin)
IGF-1
(somatomedin)
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