examorelin

{{Short description|Chemical compound}}

{{Drugbox

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| 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

| image = Hexarelin_structure.png

| width = 250px

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| routes_of_administration = Intravenous, subcutaneous, intranasal, oral{{cite journal | vauthors = Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F | title = Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 78 | issue = 3 | pages = 693–698 | date = March 1994 | pmid = 8126144 | doi = 10.1210/jcem.78.3.8126144 }}

| bioavailability =

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| elimination_half-life = ~55 minutes{{cite journal | vauthors = Imbimbo BP, Mant T, Edwards M, Amin D, Dalton N, Boutignon F, Lenaerts V, Wüthrich P, Deghenghi R | display-authors = 6 | title = Growth hormone-releasing activity of hexarelin in humans. A dose-response study | journal = European Journal of Clinical Pharmacology | volume = 46 | issue = 5 | pages = 421–425 | year = 1994 | pmid = 7957536 | doi = 10.1007/bf00191904 | s2cid = 19573322 }}

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| CAS_number = 140703-51-1

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| ATC_prefix = None

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| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 09QF37C617

| PubChem = 6918297

| ChEMBL = 108335

| IUPHAR_ligand = 1100

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| ChemSpiderID = 5293503

| C=47 | H=58 | N=12 | O=6

| smiles = 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

| StdInChI = 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

| StdInChIKey = RVWNMGKSNGWLOL-GIIHNPQRSA-N

| synonyms = L-Histidyl-2-methyl-D-tryptophyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide

}}

Examorelin (INN; also known as hexarelin; developmental codes EP-23905 and MF-6003) 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.{{cite book| vauthors = Ganellin CR, Triggle DJ |title=Dictionary of Pharmacological Agents|url=https://books.google.com/books?id=Z_mfTTIApVEC&pg=PA617|date=21 November 1996|publisher=CRC Press|isbn=978-0-412-46630-4|pages=617–}}{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA117|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=117–}}{{cite journal | vauthors = Moulin A, Ryan J, Martinez J, Fehrentz JA | title = Recent developments in ghrelin receptor ligands | journal = ChemMedChem | volume = 2 | issue = 9 | pages = 1242–1259 | date = September 2007 | pmid = 17520591 | doi = 10.1002/cmdc.200700015 | s2cid = 24945528 }}{{cite journal | vauthors = Wang Y, Tomlinson B | title = Tesamorelin, a human growth hormone releasing factor analogue | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 3 | pages = 303–310 | date = March 2009 | pmid = 19243281 | doi = 10.1517/13543780802707658 | s2cid = 71177320 }}{{cite journal | vauthors = Carpino PA | title= Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists| journal= Expert Opinion on Therapeutic Patents| volume=12 | issue=11 | year=2002 | pages=1599–1618 | doi=10.1517/13543776.12.11.1599 | s2cid=83645573 }} 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.

Examorelin substantially and dose-dependently increases plasma levels of growth hormone (GH) in animals and humans. 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.{{cite journal | vauthors = Arvat E, di Vito L, Maccagno B, Broglio F, Boghen MF, Deghenghi R, Camanni F, Ghigo E | display-authors = 6 | title = 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 | journal = Peptides | volume = 18 | issue = 6 | pages = 885–891 | year = 1997 | pmid = 9285939 | doi = 10.1016/s0196-9781(97)00016-8 | s2cid = 25480336 }} 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.{{cite journal | vauthors = Ghigo E, Arvat E, Gianotti L, Grottoli S, Rizzi G, Ceda GP, Boghen MF, Deghenghi R, Camanni F | display-authors = 6 | title = Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging | journal = European Journal of Endocrinology | volume = 135 | issue = 4 | pages = 407–412 | date = October 1996 | pmid = 8921821 | doi = 10.1530/eje.0.1350407 }}{{cite journal | vauthors = Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A | title = Intranasal administration of the GHRP hexarelin accelerates growth in short children | journal = Clinical Endocrinology | volume = 43 | issue = 5 | pages = 631–635 | date = November 1995 | pmid = 8548949 | doi = 10.1111/j.1365-2265.1995.tb02929.x | s2cid = 30980163 }}{{cite journal | vauthors = Frenkel J, Silbergeld A, Deghenghi R, Laron Z | title = Short term effect of intranasal administration of hexarelin--a synthetic growth hormone-releasing peptide. Preliminary communication | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 8 | issue = 1 | pages = 43–45 | year = 1995 | pmid = 7584696 | doi = 10.1515/jpem.1995.8.1.43 | s2cid = 6791525 }} Examorelin does not affect plasma levels of glucose, luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH) in humans.

Examorelin releases more GH than does growth hormone-releasing hormone (GHRH) in humans,{{cite journal | vauthors = Maccario M, Arvat E, Procopio M, Gianotti L, Grottoli S, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F, Ghigo E | display-authors = 6 | title = Metabolic modulation of the growth hormone-releasing activity of hexarelin in man | journal = Metabolism | volume = 44 | issue = 1 | pages = 134–138 | date = January 1995 | pmid = 7854159 | doi = 10.1016/0026-0495(95)90300-3 }} 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.{{cite journal | vauthors = Massoud AF, Hindmarsh PC, Brook CG | title = Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 81 | issue = 12 | pages = 4338–4341 | date = December 1996 | pmid = 8954038 | doi = 10.1210/jcem.81.12.8954038 | doi-access = free }}{{cite journal | vauthors = Arvat E, Di Vito L, Gianotti L, Ramunni J, Boghen MF, Deghenghi R, Camanni F, Ghigo E | display-authors = 6 | title = Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man | journal = Metabolism | volume = 46 | issue = 1 | pages = 83–88 | date = January 1997 | pmid = 9005975 | doi = 10.1016/s0026-0495(97)90173-6 }}{{cite journal | vauthors = Arvat E, Gianotti L, Di Vito L, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F, Ghigo E | display-authors = 6 | title = Modulation of growth hormone-releasing activity of hexarelin in man | journal = Neuroendocrinology | volume = 61 | issue = 1 | pages = 51–56 | date = January 1995 | pmid = 7731498 | doi = 10.1159/000126827 }} Pre-administration of GH blunts the GH-releasing effect of examorelin, while, in contrast, fully abolishing the effect of GHRH.{{cite journal | vauthors = Massoud AF, Hindmarsh PC, Brook CG | title = Hexarelin induced growth hormone release is influenced by exogenous growth hormone | journal = Clinical Endocrinology | volume = 43 | issue = 5 | pages = 617–621 | date = November 1995 | pmid = 8548947 | doi = 10.1111/j.1365-2265.1995.tb02927.x | s2cid = 31571160 }} Pre-treatment with IGF-1 also blunts the GH-elevating effect of examorelin.{{cite book| vauthors = Owusu-Apenten R | chapter = Anabolic Dysfunction |title=Bioactive Peptides: Applications for Improving Nutrition and Health| chapter-url = https://books.google.com/books?id=JJ_MBQAAQBAJ&pg=PA292|date=23 June 2010|publisher=CRC Press|isbn=978-1-4398-1363-8|pages=292–}} Testosterone, testosterone enanthate, and ethinylestradiol, though not oxandrolone, have been found to significantly potentiate the GH-releasing effects of examorelin in humans.{{cite journal | vauthors = Loche S, Colao A, Cappa M, Bellone J, Aimaretti G, Farello G, Faedda A, Lombardi G, Deghenghi R, Ghigo E | display-authors = 6 | title = The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 3 | pages = 861–864 | date = March 1997 | pmid = 9062497 | doi = 10.1210/jcem.82.3.3795 | doi-access = free }}{{cite journal | vauthors = Loche S, Cambiaso P, Carta D, Setzu S, Imbimbo BP, Borrelli P, Pintor C, Cappa M | display-authors = 6 | title = The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 2 | pages = 674–678 | date = February 1995 | pmid = 7852535 | doi = 10.1210/jcem.80.2.7852535 }} 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.{{cite journal | vauthors = Bellone J, Aimaretti G, Bartolotta E, Benso L, Imbimbo BP, Lenhaerts V, Deghenghi R, Camanni F, Ghigo E | display-authors = 6 | title = Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 4 | pages = 1090–1094 | date = April 1995 | pmid = 7714074 | doi = 10.1210/jcem.80.4.7714074 }}

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).{{cite journal | vauthors = Rahim A, O'Neill PA, Shalet SM | title = Growth hormone status during long-term hexarelin therapy | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 5 | pages = 1644–1649 | date = May 1998 | pmid = 9589671 | doi = 10.1210/jcem.83.5.4812 | doi-access = free }}{{cite book| vauthors = Ghigo E |title=Growth Hormone Secretagogues: Basic Findings and Clinical Implications|url=https://books.google.com/books?id=pDabYbzcGSQC&pg=PA178|year=1999|publisher=Elsevier|isbn=978-0-444-82933-7|pages=178–}}

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.{{cite journal | vauthors = Suckling K | title = Discontinued drugs in 2005: cardiovascular drugs | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 11 | pages = 1299–1308 | date = November 2006 | pmid = 17040192 | doi = 10.1517/13543784.15.11.1299 | s2cid = 21632578 }}