Ibutamoren

Last updated
Ibutamoren
Ibutamoren skeletal.svg
Clinical data
Other namesMK-677; MK-0677; L-163,191; Oratrope
Routes of
administration 		By mouth
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 4–6 hours (in beagles); [1] IGF-1 levels remain elevated in humans with a single oral dose for up to 24 hours [2]
Identifiers
  • 2-amino-2-methyl-N-[1-(1-methylsulfonylspiro[2H-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.236.734 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H36N4O5S
Molar mass 528.67 g·mol−1
3D model (JSmol)
  • O=S(C)(=O)N(C2)c1ccccc1C23CCN(CC3)C(=O)C(NC(=O)C(N)(C)C)COCc4ccccc4
  • InChI=1S/C27H36N4O5S/c1-26(2,28)25(33)29-22(18-36-17-20-9-5-4-6-10-20)24(32)30-15-13-27(14-16-30)19-31(37(3,34)35)23-12-8-7-11-21(23)27/h4-12,22H,13-19,28H2,1-3H3,(H,29,33)/t22-/m1/s1
  • Key:UMUPQWIGCOZEOY-JOCHJYFZSA-N
   (verify)

Ibutamoren (INN Tooltip International Nonproprietary Name) (developmental code names MK-677, MK-0677, LUM-201, L-163,191; former tentative brand name Oratrope) is a potent, long-acting, orally-active, selective, and non-peptide agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. [3] [4] [5] [6] [7] It has been shown to increase the secretion of several hormones including GH and insulin-like growth factor 1 (IGF-1) and produces sustained increases in the plasma levels of these hormones without affecting cortisol levels. [8]

Contents

Effect on lean mass

Ibutamoren has been shown to sustain activation of the GH–IGF-1 axis, increasing growth hormone secretion by up to 97%, [9] and to increase lean body mass with no change in total fat mass or visceral fat. It is under investigation as a potential treatment for reduced levels of these hormones, such as in children or elderly adults with growth hormone deficiency, [3] [10] [11] [12] and human studies have shown it to increase both muscle mass and bone mineral density, [13] [14] making it a promising potential therapy for the treatment of frailty in the elderly. [15] [16] As of June 2017, ibutamoren is in the preclinical stage of development for growth hormone deficiency. [3]

Effect on sleep architecture

In a small study of 14 subjects, MK-677 dosed at 25mg/day at bedtime was shown to increase REM sleep by 20% and 50% in young and older subjects respectively. [17] Treatment with MK-677 also resulted in an approximate 50% increase in deep sleep in young subjects. [17]

Growth hormone deficiency

In a study of children with growth hormone deficiency, MK-677 performed better than other growth hormone secretagogues at improving growth hormone levels. [18] An ongoing study compares MK-677 directly to injectable hGH in terms of height velocity in this population. [19]

Non-research use

Since MK-677 is still an Investigational New Drug, it has not yet been approved to be marketed for consumption by humans in the United States. [3] However, it has been used experimentally by some in the bodybuilding community.

See also

Related Research Articles

<span class="mw-page-title-main">Growth hormone</span> Peptide hormone, that stimulates growth

Growth hormone (GH) or somatotropin, also known as human growth hormone in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of Insulin-like growth factor 1 (IGF-1) and increases the concentration of glucose and free fatty acids. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Motilin</span>

Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.

Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by several other names in its endogenous forms and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

<span class="mw-page-title-main">Capromorelin</span> Chemical compound

Capromorelin, sold under the brand names, Entyce and Elura, is a medication used for the management of weight loss in cats and dogs. Capromorelin is a ghrelin receptor agonist known to increase appetite and weight gain.

Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined however, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.

<span class="mw-page-title-main">Growth hormone secretagogue receptor</span> Protein-coding gene in the species Homo sapiens

Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

<span class="mw-page-title-main">GHRP-6</span> Chemical compound

Growth hormone-releasing peptide 6 (GHRP-6), also known as growth hormone-releasing hexapeptide, is one of several synthetic met-enkephalin analogues that include unnatural D-amino acids, were developed for their growth hormone-releasing activity and are called growth hormone secretagogues. They lack opioid activity but are potent stimulators of growth hormone (GH) release. These secretagogues are distinct from growth hormone releasing hormone (GHRH) in that they share no sequence relation and derive their function through activation of a completely different receptor. This receptor was originally called the growth hormone secretagogue receptor (GHSR), but due to subsequent discoveries, the hormone ghrelin is now considered the receptor's natural endogenous ligand, and it has been renamed as the ghrelin receptor. Therefore, these GHSR agonists act as synthetic ghrelin mimetics.

<span class="mw-page-title-main">Growth-hormone-releasing hormone receptor</span> Receptor protein that binds with somatcrinin

The growth-hormone-releasing hormone receptor (GHRHR) is a G-protein-coupled receptor that binds growth hormone-releasing hormone. The GHRHR activates a Gs protein that causes a cascade of cAMP via adenylate cyclase. GHRHR is distinct from the growth hormone secretagogue receptor, where growth hormone releasing peptides act to release growth hormone.

CJC-1295, also known as DAC:GRF, is a synthetic analogue of growth hormone-releasing hormone (GHRH) and a growth hormone secretagogue (GHS) which was developed by ConjuChem Biotechnologies. It is a modified form of GHRH (1-29) with improved pharmacokinetics, especially in regard to half-life.

<span class="mw-page-title-main">SM-130686</span> Chemical compound

SM-130686 is a small-molecule drug which acts as a potent, orally-active agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and growth hormone secretagogue, with around half the potency of the endogenous agonist ghrelin as a stimulator of growth hormone release. It produces dose-dependent increases in muscle mass and decrease in body fat, and is under investigation for the treatment of growth hormone deficiency and other medical conditions. Concerns about its potential use as a performance-enhancing drug for athletes have led to the development of urine tests for SM-130686 and other GHSR agonists, even though no drugs from this class have yet progressed to clinical use.

<span class="mw-page-title-main">Tabimorelin</span> Chemical compound

Tabimorelin (INN) is a drug which acts as a potent, orally-active agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and growth hormone secretagogue, mimicking the effects of the endogenous peptide agonist ghrelin as a stimulator of growth hormone (GH) release. It was one of the first GH secretagogues developed and is largely a modified polypeptide, but it is nevertheless orally-active in vivo. Tabimorelin produced sustained increases in levels of GH and insulin-like growth factor 1 (IGF-1), along with smaller transient increases in levels of other hormones such as adrenocorticotropic hormone (ACTH), cortisol, and prolactin. However actual clinical effects in adults with growth hormone deficiency were limited, with only the most severely GH-deficient patients showing significant benefit, and tabimorelin was also found to act as a CYP3A4 inhibitor which could cause it to have undesirable interactions with other drugs.

Cyril Y. Bowers, M.D., emeritus professor of medicine at Tulane University School of Medicine, attended medical school at the University of Oregon and did an internship at the University of Washington. He then studied biochemistry at Cornell University and attended the postgraduate school of medicine at the University of Pennsylvania. From 1961-2004 he was the director of the Section of Endocrinology & Metabolism in the department of medicine at Tulane University School of Medicine. Bowers has served on the editorial board of several endocrine journals, was a member of the National Institute of Diabetes and Digestive and Kidney Diseases Study Section for eight years and has written over 400 articles in peer-reviewed journals, including chapters in books and over 200 abstracts.

Growth hormone secretagogues or GH secretagogues (GHSs) are a class of drugs which act as secretagogues of growth hormone (GH). They include agonists of the ghrelin/growth hormone secretagogue receptor (GHSR), such as ghrelin (lenomorelin), pralmorelin (GHRP-2), GHRP-6, examorelin (hexarelin), ipamorelin, and ibutamoren (MK-677), and agonists of the growth hormone-releasing hormone receptor (GHRHR), such as growth hormone-releasing hormone, CJC-1295, sermorelin, and tesamorelin.

<span class="mw-page-title-main">Macimorelin</span> Chemical compound

Macimorelin (INN) – or Macrilen – is a drug that was developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist. It is a growth hormone secretagogue receptor agonist, causing release of growth hormone from the pituitary gland. Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

<span class="mw-page-title-main">Pralmorelin</span> Chemical compound

Pralmorelin (INN), also known as pralmorelin hydrochloride (JAN) and pralmorelin dihydrochloride (USAN), as well as, notably, growth hormone-releasing peptide 2 (GHRP-2), is a growth hormone secretagogue (GHS) used as a diagnostic agent that is marketed by Kaken Pharmaceutical in Japan in a single-dose formulation for the assessment of growth hormone deficiency (GHD).

<span class="mw-page-title-main">Anamorelin</span> Chemical compound

Anamorelin (INN), also known as anamorelin hydrochloride, is a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) with appetite-enhancing and anabolic effects which is under development by Helsinn Healthcare SA for the treatment of cancer cachexia and anorexia.

<span class="mw-page-title-main">Examorelin</span> Chemical compound

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. 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.

Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Variations of the concentration in a certain frequency can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant (tonic) stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.

<span class="mw-page-title-main">Ulimorelin</span> Chemical compound

Ulimorelin is a drug with a modified cyclic peptide structure which acts as a selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR-1a). Unlike many related drugs, ulimorelin has little or no effect on growth hormone (GH) release in rats. However, like ghrelin and other ghrelin agonists, ulimorelin does stimulate GH release with concomitant increases in insulin-like growth factor 1 (IGF-1) in humans. It has been researched for enhancing gastrointestinal motility, especially in gastroparesis and in aiding recovery of bowel function following gastrointestinal surgery, where opioid analgesic drugs used for post-operative pain relief may worsen existing constipation. While ulimorelin has been shown to increase both upper and lower gastrointestinal motility in rats, and showed promising results initially in humans, it failed in pivotal clinical trials in post operative ileus.

References

  1. ↑ Smith RG, Thorner MO (28 January 2000). Human Growth Hormone: Research and Clinical Practice. Springer Science & Business Media. pp. 45–. ISBN   978-1-59259-015-5.
  2. ↑ Smith RG, Van der Ploeg LH, Howard AD, Feighner SD, Cheng K, Hickey GJ, et al. (October 1997). "Peptidomimetic regulation of growth hormone secretion". Endocrine Reviews. The Endocrine Society. 18 (5): 621–645. doi: 10.1210/edrv.18.5.0316 . PMID   9331545.
  3. 1 2 3 4 "Ibutamoren - Lumos Pharma/Merck". AdisInsight.
  4. ↑ Patchett AA, Nargund RP, Tata JR, Chen MH, Barakat KJ, Johnston DB, et al. (July 1995). "Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue". Proceedings of the National Academy of Sciences of the United States of America. 92 (15): 7001–7005. Bibcode:1995PNAS...92.7001P. doi: 10.1073/pnas.92.15.7001 . PMC   41459 . PMID   7624358.
  5. ↑ Pong SS, Chaung LY, Dean DC, Nargund RP, Patchett AA, Smith RG (January 1996). "Identification of a new G-protein-linked receptor for growth hormone secretagogues". Molecular Endocrinology. 10 (1): 57–61. doi: 10.1210/mend.10.1.8838145 . PMID   8838145.
  6. ↑ Cassoni P, Papotti M, Ghè C, Catapano F, Sapino A, Graziani A, et al. (April 2001). "Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines". The Journal of Clinical Endocrinology and Metabolism. 86 (4): 1738–1745. doi: 10.1210/jcem.86.4.7402 . PMID   11297611.
  7. ↑ Holst B, Frimurer TM, Mokrosinski J, Halkjaer T, Cullberg KB, Underwood CR, Schwartz TW (January 2009). "Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor". Molecular Pharmacology. 75 (1): 44–59. doi:10.1124/mol.108.049189. PMID   18923064. S2CID   2218638.
  8. ↑ Copinschi G, Van Onderbergen A, L'Hermite-Balériaux M, Mendel CM, Caufriez A, Leproult R, et al. (August 1996). "Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men". The Journal of Clinical Endocrinology and Metabolism. 81 (8): 2776–2782. doi: 10.1210/jcem.81.8.8768828 . PMID   8768828.
  9. ↑ Chapman, I. M. (1996). Stimulation of the growth hormone (gh)-insulin-like growth factor I axis by Daily Oral Administration of a GH secretogogue (MK-677) in healthy elderly subjects. Journal of Clinical Endocrinology &amp; Metabolism, 81(12), 4249–4257. https://doi.org/10.1210/jc.81.12.4249
  10. ↑ Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, et al. (December 1996). "Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects". The Journal of Clinical Endocrinology and Metabolism. 81 (12): 4249–4257. doi: 10.1210/jcem.81.12.8954023 . PMID   8954023.
  11. ↑ Thorner MO, Chapman IM, Gaylinn BD, Pezzoli SS, Hartman ML (1997). "Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging". Recent Progress in Hormone Research. 52: 215–44, discussion 244–6. PMID   9238854.
  12. ↑ Chapman IM, Pescovitz OH, Murphy G, Treep T, Cerchio KA, Krupa D, et al. (October 1997). "Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults". The Journal of Clinical Endocrinology and Metabolism. 82 (10): 3455–3463. doi: 10.1210/jcem.82.10.4297 . PMID   9329386.
  13. ↑ Murphy MG, Bach MA, Plotkin D, Bolognese J, Ng J, Krupa D, et al. (July 1999). "Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group". Journal of Bone and Mineral Research. 14 (7): 1182–1188. doi: 10.1359/jbmr.1999.14.7.1182 . PMID   10404019.
  14. ↑ Murphy MG, Weiss S, McClung M, Schnitzer T, Cerchio K, Connor J, et al. (March 2001). "Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women". The Journal of Clinical Endocrinology and Metabolism. 86 (3): 1116–1125. doi: 10.1210/jcem.86.3.7294 . PMID   11238495.
  15. ↑ Smith RG, Sun Y, Jiang H, Albarran-Zeckler R, Timchenko N (November 2007). "Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging". Annals of the New York Academy of Sciences. 1119 (1): 147–164. Bibcode:2007NYASA1119..147S. doi:10.1196/annals.1404.023. PMID   18056963. S2CID   3220799.
  16. ↑ "An Anti-frailty Pill For Seniors? New Drug Increases Muscle Mass In Arms And Legs Of Older Adults". ScienceDaily. 5 November 2008.
  17. 1 2 Copinschi G, Leproult R, Van Onderbergen A, Caufriez A, Cole KY, Schilling LM, et al. (October 1997). "Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man". Neuroendocrinology. 66 (4): 278–286. doi:10.1159/000127249. PMID   9349662.
  18. ↑ Bright GM, Thorner MO (30 March 2022). "A GH Secretagogue Receptor Agonist (LUM-201) Elicits Greater GH Responses than Standard GH Secretagogues in Subjects of a Pediatric GH Deficiency Trial". Hormone Research in Paediatrics. 95 (1): 76–81. doi:10.1159/000524244. PMC   9227666 . PMID   35354138.
  19. ↑ "Phase 2 Study of LUM-201 in Children With Growth Hormone Deficiency (OraGrowtH210 Trial) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 4 September 2023.
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