Examorelin

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
Elimination half-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
PubChem CID
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 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. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at the ghrelin receptor.[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 ethinylestradiol, 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]

  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. ^ a b c d e Imbimbo 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. ^ a b Moulin 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. ^ a b c Wang 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. ^ a b Arvat 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. ^ a b Arvat 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.