Examorelin

Examorelin
Systematic (IUPAC) name
(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
Clinical data
Routes of
administration		 Intravenous, subcutaneous, intranasal, oral[1]
Pharmacokinetic data
Biological half-life ~55 minutes[2]
Identifiers
CAS Number 140703-51-1
ATC code None
PubChem CID 6918297
IUPHAR/BPS 1100
ChemSpider 5293503
ChEMBL CHEMBL108335
Synonyms L-Histidyl-2-methyl-D-tryptophyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide
Chemical data
Formula C47H58N12O6
Molar mass 887.04022 g/mol

Examorelin (INN) (developmental code names EP-23905, MF-6003), also known as hexarelin, is a potent, synthetic, peptidic, orally-active, centrally-penetrant, and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and a growth hormone secretagogue which was developed by Mediolanum Farmaceutici.[3][4][5][6][7] It is a hexapeptide with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived from GHRP-6 (which, in turn, is an analogue of ghrelin).[5][6]

Examorelin substantially and dose-dependently increases plasma levels of growth hormone (GH) in animals and humans.[2] In addition, similarly to pralmorelin (GHRP-2) and GHRP-6, it slightly and dose-dependently stimulates the release of prolactin, adrenocorticotropic hormone (ACTH), and cortisol in humans.[2][8] There are conflicting reports on the ability of examorelin to elevate insulin-like growth factor 1 (IGF-1) and insulin-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 of glucose, luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH) in humans.[2]

Examorelin releases more GH than does growth 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, and ethinyl estradiol, though not oxandrolone, have been found to significantly potentiate the GH-releasing effects of examorelin in humans.[18][19] In accordance, likely due to increases in sex 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 reached phase II clinical trials for the treatment of growth hormone deficiency and congestive heart failure but did not complete development and was never marketed.[6][23][24]

See also

References

  1. ↑ Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, et al. (1994). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man.". J Clin Endocrinol Metab 78 (3): 693–8. doi:10.1210/jcem.78.3.8126144. PMID 8126144.
  2. 1 2 3 4 5 Imbimbo, B.P.; Mant, T.; Edwards, M.; Amin, D.; Dalton, N.; Boutignon, F.; Lenaerts, V.; W�thrich, P.; Deghenghi, R. (1994). "Growth hormone-releasing activity of hexarelin in humans". Eur J Clin Pharmacol (Springer Science $\mathplus$ Business Media) 46 (5). doi:10.1007/bf00191904. Retrieved 2015-06-12.
  3. ↑ C.R. Ganellin; David J. Triggle (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 617–. ISBN 978-0-412-46630-4.
  4. ↑ I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 117–. ISBN 978-94-011-4439-1.
  5. 1 2 Moulin A, Ryan J, Martinez J, Fehrentz JA (2007). "Recent developments in ghrelin receptor ligands.". ChemMedChem 2 (9): 1242–59. doi:10.1002/cmdc.200700015. PMID 17520591.
  6. 1 2 3 Wang Y, Tomlinson B (2009). "Tesamorelin, a human growth hormone releasing factor analogue.". Expert Opin Investig Drugs 18 (3): 303–10. doi:10.1517/13543780802707658. PMID 19243281.
  7. ↑ Carpino, Philip A (2002). "Recent developments in ghrelin receptor (GHS)". Expert Opin. Ther. Patents (Informa Healthcare) 12 (11): 1599–1618. doi:10.1517/13543776.12.11.1599. Retrieved 2015-06-12.
  8. 1 2 Arvat, Emanuela; Vito, Lidia Di; Maccagno, Barbara; Broglio, Fabio; Boghen, Muni F; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1997). "Effects of GHRP". Peptides (Elsevier BV) 18 (6): 885–891. doi:10.1016/s0196-9781(97)00016-8. Retrieved 2015-06-12.
  9. ↑ Ghigo, E; Arvat, E; Gianotti, L; Grottoli, S; Rizzi, G; Ceda, G.; Boghen, M.; Deghenghi, R; Camanni, F (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 (BioScientifica) 135 (4): 407–412. doi:10.1530/eje.0.1350407. Retrieved 2015-06-12.
  10. ↑ Laron, Z.; Frenkel, J.; Deghenghl, R.; Anin, S.; Klinger, B.; Siibergeld, A. (1995). "Intranasal administration of the GHRP". Clinical Endocrinology (Wiley-Blackwell) 43 (5): 631–635. doi:10.1111/j.1365-2265.1995.tb02929.x. Retrieved 2015-06-12.
  11. ↑ Frenkel, J.; Silbergeld, A.; Deghenghi, R.; Laron, Z. (1995). "Short Term Effect of Intranasal Administration of Hexarelin". Journal of Pediatric Endocrinology and Metabolism (Walter de Gruyter (GmbH)) 8 (1). doi:10.1515/jpem.1995.8.1.43. Retrieved 2015-06-12.
  12. ↑ Maccario, M.; Arvat, E.; Procopio, M.; Gianotti, L.; Grottoli, S.; Imbimbo, B.P.; Lenaerts, V.; Deghenghi, R.; Camanni, F.; Ghigo, E. (1995). "Metabolic modulation of the growth hormone-releasing activity of hexarelin in man". Metabolism (Elsevier BV) 44 (1): 134–138. doi:10.1016/0026-0495(95)90300-3. Retrieved 2015-06-12.
  13. ↑ Massoud, A F; Hindmarsh, P C; Brook, C G (1996). "Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study.". The Journal of Clinical Endocrinology (The Endocrine Society) 81 (12): 4338–4341. doi:10.1210/jcem.81.12.8954038. Retrieved 2015-06-12.
  14. 1 2 Arvat, Emanuela; Vito, Lidia Di; Gianotti, Laura; Ramunni, Josefina; Boghen, Muni F.; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1997). "Mechanisms underlying the negative growth hormone (GH)". Metabolism (Elsevier BV) 46 (1): 83–88. doi:10.1016/s0026-0495(97)90173-6. Retrieved 2015-06-12.
  15. ↑ Arvat, Emanuela; Gianotti, Laura; Vito, Lidia Di; Imbimbo, Bruno P.; Lenaerts, Vincent; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1995). "Modulation of Growth Hormone-Releasing Activity of Hexarelin in Man". Neuroendocrinology (S. Karger (AG)) 61 (1): 51–56. doi:10.1159/000126827. Retrieved 2015-06-12.
  16. ↑ Massoud, Ahmed F.; Hindmarsh, Peter C.; Brook, Charles G. D. (1995). "Hexarelin induced growth hormone release is influenced by exogenous growth hormone". Clinical Endocrinology (Wiley-Blackwell) 43 (5): 617–621. doi:10.1111/j.1365-2265.1995.tb02927.x. Retrieved 2015-06-12.
  17. ↑ Richard Owusu-Apenten (23 June 2010). 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. (1997). "The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids.". J Clin Endocrinol Metab 82 (3): 861–4. doi:10.1210/jcem.82.3.3795. PMID 9062497.
  19. ↑ Loche, S; Cambiaso, P; Carta, D; Setzu, S; Imbimbo, B P; Borrelli, P; Pintor, C; Cappa, M (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 (The Endocrine Society) 80 (2): 674–678. doi:10.1210/jcem.80.2.7852535. Retrieved 2015-06-12.
  20. ↑ Bellone, J; Aimaretti, G; Bartolotta, E; Benso, L; Imbimbo, B P; Lenhaerts, V; Deghenghi, R; Camanni, F; Ghigo, E (1995). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty.". The Journal of Clinical Endocrinology (The Endocrine Society) 80 (4): 1090–1094. doi:10.1210/jcem.80.4.7714074. Retrieved 2015-06-12.
  21. ↑ Rahim A, O'Neill PA, Shalet SM (1998). "Growth hormone status during long-term hexarelin therapy". J. Clin. Endocrinol. Metab. 83 (5): 1644–9. doi:10.1210/jcem.83.5.4812. PMID 9589671.
  22. ↑ Ezio Ghigo (1999). Growth Hormone Secretagogues: Basic Findings and Clinical Implications. Elsevier. pp. 178–. ISBN 978-0-444-82933-7.
  23. ↑ Wiesmann UN, DiDonato S, Herschkowitz NN (1975). "Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake.". Biochem Biophys Res Commun 66 (4): 1338–43. doi:10.1016/0006-291x(75)90506-9. PMID 4.
  24. ↑ Suckling K (2006). "Discontinued drugs in 2005: cardiovascular drugs.". Expert Opin Investig Drugs 15 (11): 1299–308. doi:10.1517/13543784.15.11.1299. PMID 17040192.
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