What Has Published Research Reported About MK-677?

What is MK-677?

MK-677 is an orally active growth hormone secretagogue, a compound that stimulates growth hormone (GH) release, and unlike most compounds profiled on this blog it is not a peptide. It is also written MK-0677 or ibutamoren, and its first description used the code L-163,191, with MK-0677 naming the mesylate salt (source 2). Jacks and colleagues described it in 1996 as a spiroindoline sulfonamide (source 3). An earlier nonpeptide secretagogue from the same company, L-692,429, had been reported in Science in 1993 by Smith and colleagues at Merck Research Laboratories, who described it as a benzolactam-type molecule (source 1).

Compound reference listings give the free base the formula C27H36N4O5S. Calculated from that formula, the average mass is about 528.7 daltons, and a mesylate salt carrying one methanesulfonic acid calculates to about 624.8 daltons. These are calculated values rather than figures quoted from a cited paper, and the difference between the two forms matters for laboratories, as discussed at the end of this profile.

This Steadfast Research Group profile summarizes what the primary literature reported about MK-677, from its cell and animal pharmacology to the small human studies of the late 1990s and 2000s. It is written for researchers reading that record and covers published observations only. The peptide secretagogues it was compared with are covered in the GHRP-6, hexarelin and ipamorelin profiles.

How did the first studies describe MK-677’s activity?

The design paper appeared in PNAS in 1995, from Patchett, Nargund, Tata and colleagues at Merck (source 2). In cultured rat pituitary cells, the authors reported that L-163,191 released GH with an EC50 of about 1.3 nM, and they described a mechanism indistinguishable from that of GHRP-6 and L-692,429 but distinct from that of GHRH. In dogs, oral administration raised GH, and the release was described as specific: at the amount tested there was no significant effect on aldosterone, luteinizing hormone, thyroxine or prolactin, and cortisol rose only modestly. On the strength of these properties the compound was selected for clinical studies (source 2).

Jacks and colleagues followed in Endocrinology in 1996 with a study in beagles that measured GH, insulin-like growth factor I (IGF-I) and other hormonal responses after single oral and intravenous administration (source 3). A 1997 study by Hickey and colleagues in the Journal of Endocrinology turned to repeated administration. The authors reported that IGF-I rose by as much as 126 percent and stayed elevated through 14 days of daily administration, that cortisol secretion also increased, and that a regulatory feedback loop apparently limited hyperstimulation of the GH axis (source 4).

A 1999 study by Schleim and colleagues asked whether the IGF-I rise was a direct effect. Beagles received MK-0677 orally before and after either hypophysectomy, the surgical removal of the pituitary, or sham surgery (source 5). After hypophysectomy, mean peak GH was unchanged following MK-0677 and serum IGF-I fell by at least half, and the title reported that the increases in circulating IGF-I depended upon pituitary mediation (source 5). In the dog, then, the reported IGF-I response ran through the pituitary rather than around it.

Which receptor does MK-677 act at?

The 1993 Science paper on L-692,429 reported that the nonpeptide compound synergized with the natural secretagogue GHRH and acted through an alternative signal transduction pathway, and the authors argued from studies with peptidyl and nonpeptidyl antagonists that it mimicked the hexapeptide GHRP-6 (source 1). The 1995 paper on MK-677 repeated the comparison at the cellular level, as described above (source 2).

The receptor itself was reported in 1996. Howard and colleagues described in Science a G protein-coupled receptor in the pituitary and hypothalamus that functioned in GH release and served as the target of synthetic GH secretagogues (source 6). The same year, Pong and colleagues, including Nargund, Patchett and Smith, reported a new G-protein-linked receptor for GH secretagogues in Molecular Endocrinology (source 7). In 1999, Kojima and colleagues purified the endogenous ligand from rat stomach, a 28-amino-acid peptide with an n-octanoyl group on serine 3 that released GH, and named it ghrelin (source 8).

MK-677 therefore predates ghrelin by four years. When a randomized trial of the compound was published in 2008, its title called MK-677 an oral ghrelin mimetic (source 11), a label that could only be applied after the natural ligand had been found.

What did studies in older adults report?

The first human study of daily oral administration was published by Chapman and colleagues in 1996 (source 9). It was randomized, double-blind and placebo-controlled, in 32 older volunteers aged 64 to 81, with administration once daily over two study periods of 14 and 28 days. At the highest of the three amounts tested, mean 24-hour GH concentration rose 97 ± 23 percent compared with baseline, which the authors attributed to augmentation of existing pulsatile GH secretion. Mean serum IGF-I reached the normal range for young adults. Fasting glucose and IGF-binding protein-3 also rose (source 9).

Murphy and colleagues pooled three placebo-controlled studies of 187 adults aged 65 and older, some of them functionally impaired, and measured markers of bone turnover (source 10). In the group without impairment, two weeks of administration increased mean urinary N-telopeptide (NTX), a resorption marker, by 10 and 17 percent at two amounts. In functionally impaired adults, nine weeks of administration increased mean serum osteocalcin by 29.4 percent, bone-specific alkaline phosphatase by 10.4 percent and urinary NTX by 22.6 percent. The authors concluded that markers of both resorption and formation were raised, and the paper did not establish whether this would translate into a change in bone mass (source 10).

The largest and longest study was published in Annals of Internal Medicine in 2008 by Nass and colleagues (source 11). It enrolled 65 adults aged 60 to 81 in a double-blind, placebo-controlled, modified-crossover design, with fat-free mass and abdominal visceral fat as primary end points after one year. The authors reported that GH and IGF-I rose to the levels of young adults, that fat-free mass rose in the MK-677 group while it fell in the placebo group, that fasting glucose rose, and that insulin sensitivity fell. They also noted that the study was underpowered for functional end points (source 11).

What did studies in obese and GH-deficient subjects report?

Svensson and colleagues studied obese subjects in a randomized, double-blind, placebo-controlled trial lasting two months (source 12). Serum IGF-I was about 40 percent higher than with placebo (P < 0.001), and GH and prolactin were raised after the first administration, with most of those increases still present at 2 and 8 weeks. Fat-free mass showed a sustained increase and basal metabolic rate a transient one, while total and visceral fat were not significantly changed. Cortisol in serum and urine was not increased at 2 and 8 weeks, and an oral glucose tolerance test showed impaired glucose homeostasis at both time points (source 12).

A 1997 study from Chapman, Pescovitz and colleagues enrolled nine severely GH-deficient adults who received rising amounts in sequence (source 13). The GH response was larger in the subjects who were least GH- and IGF-I-deficient at baseline, and the title described stimulation of the GH/IGF-I axis in selected GH-deficient adults (source 13).

What terms recur in the MK-677 literature?

Growth hormone secretagogue

A compound that stimulates GH release. MK-677 and L-692,429 were described as nonpeptide examples (sources 1 and 2).

Ghrelin mimetic

The label used in the 2008 trial title for MK-677, applicable after ghrelin was identified as the natural ligand of the secretagogue receptor (sources 8 and 11).

IGF-I

Insulin-like growth factor I, the downstream marker measured in nearly every MK-677 study (sources 3, 4, 9 and 12).

Hypophysectomy

Surgical removal of the pituitary, used in dogs to test whether the IGF-I rise needed the pituitary (source 5).

Fat-free mass

Body mass other than fat, the primary end point in the 2008 trial and a measured outcome in the obese-subject study (sources 11 and 12).

What remains unresolved in the MK-677 literature?

The human record is short and small. The longest studies described here ran for two months in obese subjects and for one year of primary follow-up in the 2008 trial, the first study in older volunteers involved 32 people over weeks of administration, and the bone work measured biochemical markers rather than bone itself (sources 9, 10, 11 and 12). The authors of the 2008 trial noted that it lacked the power to evaluate functional end points (source 11).

Results also differed between studies. The obese-subject trial reported no significant change in total or visceral fat while fat-free mass rose, and the 2008 trial reported higher fat-free mass in older adults (sources 11 and 12). Cortisol secretion rose in the repeated-administration dog study but cortisol was not increased in the obese subjects at 2 and 8 weeks (sources 4 and 12). One finding was consistent across three human papers: each reported a change in glucose handling, as raised fasting glucose, impaired glucose tolerance or reduced insulin sensitivity (sources 9, 11 and 12).

Finally, the founding papers came from the group that developed the compound. The 1993 and 1995 papers were written at Merck Research Laboratories (sources 1 and 2), so early characterization was not independent of the developer.

How can a laboratory confirm the identity of MK-677?

MK-677 has no amino acid sequence, so the sequence-based mass calculations used for peptides do not apply. Identity is instead checked against the structure and formula, and the calculated mass depends on the form supplied: about 528.7 daltons for the free base and about 624.8 daltons for a mesylate salt. A Certificate of Analysis should say which form was tested, because the gap of roughly 96 daltons is the mass of the methanesulfonic acid counterion, not an impurity. Mass spectrometry confirms identity and HPLC measures purity. Analytical groups have also published work on the compound itself, including a 2022 study of its metabolism in vitro and in urine and plasma from horses (source 14).

The Steadfast Research Group guide to verifying research material quality covers counterion and water content in more detail.