MK-677 Research, Specifications & Scientific Information

MK-677, also named ibutamoren, is an orally active non-peptide agonist at the growth hormone secretagogue receptor GHS-R1a. Merck developed it through multiple phase 2 trials, the largest of which did not meet their primary endpoints, and development was discontinued. It is not approved by the FDA for any indication.

By Published Updated

Category: Peptide-adjacent research compounds

Introduction

MK-677 is the compound in this library with the most complete human evidence and the least favourable one, and those two facts are connected.

Merck designed it in the early 1990s to solve a specific problem. The growth hormone-releasing peptides released growth hormone reliably but had to be injected. MK-677 is a non-peptide spiroindoline that activates the same receptor and is orally bioavailable [1]. It worked, in the sense that matters for a mechanism: every trial in the clinical programme showed a large, consistent rise in serum insulin-like growth factor 1.

What the programme did not show was clinical benefit. In 563 patients with Alzheimer's disease over twelve months, there was no significant difference from placebo on any of four measures despite unambiguous target engagement [7]. In a two-year trial in healthy older adults, fat-free mass rose and strength and function did not, while fasting glucose rose and insulin sensitivity fell [6]. A phase 2b hip fracture trial was terminated early after a congestive heart failure signal [8]. Development was discontinued.

This page sets out that record. It describes research. It does not describe use in people or animals, and it contains no guidance of any kind on handling the material.

What Is MK-677?

A small molecule, not a peptide. MK-677 carries the International Nonproprietary Name ibutamoren and the development codes MK-0677 and L-163,191. Chemically it is a spiroindoline — a spiro-fused indoline and piperidine core carrying a methanesulfonyl group, a benzyl ether and an aminoisobutyramide — with molecular formula C27H36N4O5S and a molecular weight of 528.7 g/mol.

It belongs in this library under peptide-adjacent research compounds because of what it binds, not what it is made of: it is an agonist at the same receptor as GHRP-6, GHRP-2, hexarelin and ipamorelin. The design brief was explicitly peptidomimetic — reproduce that pharmacology in a molecule that survives the gut [1].

Two register records exist and the distinction is practical. The free base is UNII GJ0EGN38UL, CAS 159634-47-6. Ibutamoren mesylate, the salt used throughout the clinical programme, is UNII R90JB6QJ2B, CAS 159752-10-0, with a molecular weight of 624.77 g/mol. The difference is about 96 daltons, and a figure quoted without saying which form is meant is ambiguous by roughly 18 per cent.

It is not an approved medicine anywhere, and Merck's development programme was discontinued.

MK-677 Specifications

Compound name
MK-677
Full chemical name
2-Amino-2-methyl-N-[(2R)-1-(1-methylsulfonylspiro[2H-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide
Aliases
ibutamoren, ibutamoren mesylate, MK-0677, L-163,191
Development code
MK-0677 (also L-163,191)
CAS number
159634-47-6
PubChem CID
178024
UNII
GJ0EGN38UL
Compound type
Non-peptide small molecule (spiroindoline); orally active growth hormone secretagogue
Peptide family
Not applicable — a peptidomimetic small molecule, not a peptide
Amino acid sequence
Not publicly characterised
Sequence length
Not publicly characterised
Molecular formula
C27H36N4O5S
Molecular weight
528.7 g/mol
Primary target
Growth hormone secretagogue receptor type 1a (GHS-R1a, the ghrelin receptor)
Secondary targets
Not publicly characterised
Receptor family
Class A G protein-coupled receptor
Agonist / antagonist status
Agonist at GHS-R1a

MK-677 is not a peptide. It is a spiroindoline small molecule carrying the International Nonproprietary Name ibutamoren, recorded in the FDA/NCATS Global Substance Registration System under UNII GJ0EGN38UL with CAS registry number 159634-47-6, PubChem compound identifier 178024, molecular formula C27H36N4O5S and a molecular weight of 528.7 g/mol. The clinical literature almost always used the mesylate salt, ibutamoren mesylate, which is a separate register record — UNII R90JB6QJ2B, CAS registry number 159752-10-0, PubChem compound identifier 6450830, formula C27H36N4O5S·CH4O3S and a molecular weight of 624.77 g/mol. The two differ by one molecule of methanesulfonic acid, roughly 96 daltons, and a stated amount refers to different quantities of the active moiety depending on which form is meant. The molecule was designed as a peptidomimetic: it reproduces the receptor activity of the growth hormone-releasing peptides while being orally bioavailable, which peptides of that series are not. The amino acid sequence and sequence length fields are blank because the compound has neither.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does MK-677 Work?

Through the growth hormone secretagogue receptor type 1a, a class A G protein-coupled receptor expressed on pituitary somatotrophs and in the hypothalamus.

The history of that receptor is worth following, because it runs backwards from the usual order. The synthetic secretagogues came first, in the 1980s, as structure-activity work on met-enkephalin analogues that happened to release growth hormone. The receptor they act at was cloned in 1996 from pituitary and hypothalamus, using the synthetic compounds as the probe [2]. Only in 1999 was the endogenous ligand found — ghrelin, an acylated peptide from stomach [4]. So the receptor is now generally called the ghrelin receptor, and MK-677 is generally called a ghrelin mimetic, although the compound predates the hormone's discovery.

Activating the receptor increases pulsatile growth hormone secretion. Circulating insulin-like growth factor 1 rises as a consequence, and it is insulin-like growth factor 1 rather than growth hormone itself that the trials used as their pharmacodynamic marker, because growth hormone is secreted in pulses and a single measurement of it says very little.

The important point for reading the rest of this page is that this mechanism was never in doubt. Every trial confirmed it. The question the trials asked was whether raising the axis produces clinical benefit, and that question has a different answer.

MK-677 Mechanism of Action

In vitro research

The discovery paper reported the design of the molecule and its biological activity as a potent, orally active growth hormone secretagogue, with receptor-level and whole-animal characterisation in the same publication [1]. The compound was one of the two synthetic ligands used to clone and characterise the receptor itself, which is how a receptor gets identified when the natural ligand is unknown: the drug becomes the reagent [2].

Three years later the natural ligand was isolated from stomach and shown to be an acylated 28-residue peptide, establishing that the synthetic secretagogues had been occupying an endocrine receptor with a real hormone behind it rather than a pharmacological curiosity [4].

The in vitro record for this compound is therefore short and settled. The receptor is identified, the compound is an agonist at it, and nothing in the later clinical literature disputes either statement.

What Is MK-677 Being Researched For?

Past tense in most cases. Merck's programme covered:

  • Alzheimer's disease — a 563-patient, 12-month, double-blind multicentre trial, the largest in the programme [7, 9].
  • Functional rehabilitation after hip fracture — two randomised placebo-controlled trials, one of them terminated early [5, 8, 10].
  • Body composition and function in older adults — a two-year randomised trial [6, 11].
  • Growth hormone-deficient adults — pharmacology of the growth hormone and insulin-like growth factor 1 axis [3].

Independent registered work has continued at a much smaller scale, including a completed phase 2 study of twelve participants in non-alcoholic fatty liver disease [12].

Every one of those studies examined pharmaceutical investigational material administered under a protocol in a defined population under clinical supervision. None of it concerns research-grade material supplied for laboratory use, and none of it supports any conclusion about such material.

Human Research on MK-677

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Growth hormone-deficient adults

Oral administration stimulated the growth hormone and insulin-like growth factor 1 axis in selected growth hormone-deficient adults, establishing that the oral route reproduced the endocrine effect of the injected peptides in a population where the axis is impaired [3].

Two years in healthy older adults

Population and design. 65 healthy adults aged 60 to 81 — men, women receiving hormone replacement, and women not receiving it — in a two-year, double-blind, randomised, placebo-controlled, modified-crossover trial of 25 mg orally once daily. Primary endpoints at one year were fat-free mass and abdominal visceral fat; secondary endpoints covered body weight, fat mass, insulin sensitivity, lipids, cortisol, bone mineral density, limb composition, isokinetic strength, function and quality of life [6, 11].

Endocrine result. Growth hormone and insulin-like growth factor 1 rose significantly, into the range of healthy young adults, without serious adverse events [6].

Body composition result. Mean fat-free mass fell by 0.5 kg on placebo and rose by 1.1 kg on the compound (p < 0.001), with body cell mass following the same pattern (p = 0.021). Abdominal visceral fat and total fat mass showed no significant difference between groups; the average increase in limb fat was greater on the compound (1.1 kg against 0.24 kg; p = 0.001). Body weight rose 0.8 kg on placebo and 2.7 kg on the compound (p = 0.003) [6].

The result that matters most. Increased fat-free mass did not result in changes in strength or function. That sentence is the authors' own, and it is the single most important line in the trial: the intervention changed the marker it was designed to change and did not change the outcome that marker was supposed to predict.

Metabolic and other findings. Fasting blood glucose rose by an average of 0.3 mmol/L (p = 0.015) and insulin sensitivity decreased. Serum cortisol rose by 47 nmol/L (p = 0.020). Low-density lipoprotein cholesterol fell relative to baseline (p = 0.026), with no between-group differences in total or high-density lipoprotein cholesterol. Bone mineral density changes consistent with increased remodelling occurred [6].

Adverse effects. Most frequently an increase in appetite that subsided within a few months, and transient mild lower-limb oedema and muscle pain [6].

Limitations, as stated by the authors. Study power — both duration and participant number — was insufficient to evaluate functional endpoints in healthy elderly people.

Alzheimer's disease: the largest trial, and a negative one

Population and design. 563 patients with mild to moderate Alzheimer's disease randomised to 25 mg daily or placebo for 12 months in a double-blind multicentre study; 416 completed treatment and 12-month assessment. Efficacy measures were the clinician's interview-based impression of change with caregiver input, the cognitive subscale of the Alzheimer's Disease Assessment Scale, an activities-of-daily-living scale, and the Clinical Dementia Rating sum of boxes [7, 9].

Target engagement. Serum insulin-like growth factor 1 rose 60.1% at six weeks and 72.9% at twelve months [7].

Result. No significant differences between groups on any of the four measures over twelve months [7].

Why this trial is decisive rather than merely disappointing. The rationale was explicit and biologically grounded: insulin-like growth factor 1 increases clearance of beta-amyloid in animals, serum concentrations fall with age and fall further in Alzheimer's disease, and this compound raises them. The trial raised them by 73 per cent and nothing happened. A negative trial with demonstrated target engagement tests the hypothesis rather than the delivery, which is what makes it informative.

Hip fracture: two trials, no functional benefit

The 2004 trial. 161 previously ambulatory patients aged 65 and over, recruited 3 to 14 days after surgery at thirteen centres in seven countries, randomised to six months of daily administration or placebo and followed for a further six months. Serum insulin-like growth factor 1 rose 84% against 17% on placebo. There were no significant differences in functional performance measures or in the overall Sickness Impact Profile score. Three of four lower-limb measures, the physical domain of the Sickness Impact Profile and the ability to live independently favoured the compound without reaching significance. The authors concluded it was uncertain whether clinically significant effects on physical function were achieved, and offered two readings: that the outcome measures may not be responsive enough, or that stimulating growth hormone may simply not produce functional improvement [5].

The 2011 phase 2b trial. 123 elderly hip fracture patients randomised to 25 mg daily (n = 62) or placebo (n = 61). Insulin-like growth factor 1 rose by 51.4 ng/mL against placebo (p < 0.001). At 24 weeks, mean stair-climbing power rose by 12.5 W (95% CI −10.95 to 35.88; p = 0.292) — not significant. Gait speed showed a 0.7-score difference in means (95% CI 0.17 to 1.28; p = 0.011). Most other functional measures showed no improvement. Fewer falls occurred in the treated group without reaching significance (p = 0.096) [8, 10].

Termination. The trial was terminated early because of a safety signal of congestive heart failure in a limited number of patients. The authors' conclusion is quoted rather than paraphrased in substance: the rise in plasma insulin-like growth factor 1 was not paralleled by improvement in most functional performance measures, and the compound has an unfavourable safety profile in that patient population [8].

The overall human record

Four randomised controlled trials, consistent target engagement, no primary endpoint met, one early termination for a cardiac safety signal, and adverse metabolic changes in the longest study. Development was discontinued and no approval exists anywhere.

Preclinical Research on MK-677

Animal research

The animal work in this literature is largely confined to the discovery characterisation, because the compound moved into human studies quickly and the substantive questions were asked there.

The discovery publication reported the design of the molecule together with its biological activities as a potent, orally active growth hormone secretagogue, including the in vivo demonstration of oral activity that distinguished it from the injected peptides of the same pharmacological class [1].

The later animal rationale that motivated the Alzheimer's trial was not about this compound at all: it was the observation that insulin-like growth factor 1 increases clearance of beta-amyloid from the central nervous system in animals [7]. That is an argument about a downstream hormone, one step removed from the compound, and the human trial that tested it was negative.

Findings described in this section were observed in animals, and nothing in them establishes anything about humans — a point this compound illustrates unusually directly, since the animal-derived rationale was tested in a large human trial and did not hold.

Current Research Status

Regulatory status (United States)
Not approved. MK-677, also named ibutamoren, has not been approved by the U.S. Food and Drug Administration for any indication. Development by Merck was discontinued. Orphan designations exist against the mesylate salt, which are development incentives and not approvals.
Investigational status
Development discontinued. The compound progressed through a substantial clinical programme: phase 2 trials in Alzheimer's disease, in patients rehabilitating after hip fracture, in fibromyalgia and in body composition in older adults, together with pharmacology studies in growth hormone-deficient adults. The two largest efficacy trials reported negative primary outcomes, and one hip fracture study was terminated early after a safety signal of congestive heart failure. A small phase 2 study in non-alcoholic fatty liver disease completed in recent years.
Highest research phase reached
Phase 2 (multiple completed and reported trials; primary endpoints not met in the largest, one study terminated early for a safety signal)
Approved uses
None
Approval is compound-specific
No

Status as of . This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

Chemical & Molecular Characteristics

Two register records, and the trials used the second. The free base is UNII GJ0EGN38UL, CAS registry number 159634-47-6, PubChem compound identifier 178024, molecular formula C27H36N4O5S, molecular weight 528.7 g/mol. Ibutamoren mesylate is UNII R90JB6QJ2B, CAS registry number 159752-10-0, PubChem compound identifier 6450830, formula C27H36N4O5S·CH4O3S, molecular weight 624.77 g/mol. The clinical literature refers to 25 mg of the mesylate.

The mass difference is not trivial. One methanesulfonic acid is about 96 daltons on a 529-dalton molecule, so the salt is roughly 18 per cent heavier. A quantity stated without specifying the form is correspondingly ambiguous in its active-moiety content.

The sequence fields are blank because there is no sequence. This is a synthetic organic molecule containing a spiro-fused indoline-piperidine system, a methanesulfonamide, a benzyl ether and a 2-aminoisobutyramide. It is described here as peptide-adjacent because it shares a receptor with the growth hormone-releasing peptides; the chemistry has nothing in common with theirs.

Register breadth reflects development history. The record carries an International Nonproprietary Name, an RxNorm concept identifier, ChEMBL and EPA CompTox identifiers, and — for the mesylate — FDA and European orphan designations. Those are the marks of a compound that went through formal pharmaceutical development and are recorded here as identity facts. An orphan designation is granted on rarity and rationale, long before any efficacy determination, and this compound never received one.

Frequently Asked Questions

What is MK-677?
A non-peptide small molecule with the International Nonproprietary Name ibutamoren, developed by Merck under the codes MK-0677 and L-163,191. It was designed as a peptidomimetic of the growth hormone-releasing peptides: a molecule that activates the same receptor while being orally bioavailable, which those peptides are not [1]. The FDA/NCATS register carries it under UNII GJ0EGN38UL with CAS registry number 159634-47-6.
Is MK-677 a peptide?
No. It is a spiroindoline small molecule of molecular formula C27H36N4O5S and molecular weight 528.7 g/mol. It appears in this library under peptide-adjacent research compounds because it acts at the same receptor as the growth hormone-releasing peptides, not because it shares their chemistry. The sequence fields in the specification table are blank because the compound has no sequence.
How does MK-677 work?
It is an agonist at the growth hormone secretagogue receptor type 1a, a class A G protein-coupled receptor expressed on pituitary somatotrophs and in the hypothalamus. That receptor was cloned in 1996 as the target of the synthetic secretagogues [2], and the endogenous peptide that occupies it, ghrelin, was identified from stomach three years later [4]. Activating it increases pulsatile growth hormone secretion, and the consequent rise in circulating insulin-like growth factor 1 is the marker used in every trial on this page.
Is MK-677 FDA approved?
No. MK-677 has not been approved by the U.S. Food and Drug Administration for any indication, and Merck's development programme was discontinued. Orphan designations recorded against the mesylate salt are development incentives granted before any approval decision and are not approvals.
What did the clinical trials find?
Consistent target engagement and largely negative clinical outcomes. Serum insulin-like growth factor 1 rose in every trial. In 563 patients with mild to moderate Alzheimer's disease over 12 months, there were no significant differences from placebo on any of four efficacy measures [7]. In a two-year trial in 65 healthy older adults, fat-free mass increased significantly but strength and function did not change, while fasting glucose rose and insulin sensitivity fell [6]. In patients rehabilitating after hip fracture, two randomised trials found no improvement on most functional measures [5, 8]. The full figures are in the human research section of this page.
Why was development discontinued?
The published record supplies two reasons and this page does not go beyond it. The largest efficacy trial, in Alzheimer's disease, reported no effect on progression despite clear target engagement [7]. The phase 2b hip fracture trial was terminated early because of a safety signal of congestive heart failure in a limited number of patients, and its authors wrote that the compound has an unfavourable safety profile in that population [8].
What adverse effects were reported in the trials?
In the two-year trial in healthy older adults, the most frequent were transient mild lower-limb oedema, myalgia, and a change in hunger that subsided within a few months. Fasting blood glucose rose by an average of 0.3 mmol/L and insulin sensitivity decreased; serum cortisol rose by 47 nmol/L. The full adverse-event description is in the human research section of this page [6]. In the phase 2b hip fracture study, a congestive heart failure signal in a limited number of patients led to early termination [8].
What identifiers are published for MK-677?
For the free base: UNII GJ0EGN38UL, CAS registry number 159634-47-6, PubChem compound identifier 178024, formula C27H36N4O5S, 528.7 g/mol. For the mesylate salt used in the clinical trials: UNII R90JB6QJ2B, CAS registry number 159752-10-0, PubChem compound identifier 6450830, formula C27H36N4O5S·CH4O3S, 624.77 g/mol. The two differ by about 96 daltons, so a stated quantity means different amounts of active moiety depending on which form is meant.

Scientific References

  1. Patchett AA, Nargund RP, Tata JR, et al.. 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; 1995. PMID 7624358 doi:10.1073/pnas.92.15.7001
  2. Howard AD, Feighner SD, Cully DF, et al.. A receptor in pituitary and hypothalamus that functions in growth hormone release Science (New York, N.Y.); 1996. PMID 8688086 doi:10.1126/science.273.5277.974
  3. Chapman IM, Pescovitz OH, Murphy G, et al.. 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; 1997. PMID 9329386 doi:10.1210/jcem.82.10.4297
  4. Kojima M, Hosoda H, Date Y, et al.. Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature; 1999. PMID 10604470 doi:10.1038/45230
  5. Bach MA, Rockwood K, Zetterberg C, et al.. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture Journal of the American Geriatrics Society; 2004. PMID 15066065 doi:10.1111/j.1532-5415.2004.52156.x
  6. Nass R, Pezzoli SS, Oliveri MC, et al.. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial Annals of internal medicine; 2008. PMID 18981485 doi:10.7326/0003-4819-149-9-200811040-00003
  7. Sevigny JJ, Ryan JM, van Dyck CH, et al.. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial Neurology; 2008. PMID 19015485
  8. Adunsky A, Chandler J, Heyden N, et al.. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study Archives of gerontology and geriatrics; 2011. PMID 21067829 doi:10.1016/j.archger.2010.10.004
  9. Study of MK0677 for the Treatment of Alzheimer's Disease (0677-030)(COMPLETED) 2003. NCT00074529
  10. Treatment of Sarcopenia in Post-Hip Fracture Patients (0677-032) 2005. NCT00128115
  11. Effects of an Oral GH Secretagogue (MK-677) on Body Composition and Functional Ability of Older Adults 1998. NCT00474279
  12. The Impact of Ibutamoren on Nonalcoholic Fatty Liver Disease 2022. NCT05364684

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.