MK-677 (Ibutamoren)

MK-677, also written MK677 or MK 677, is ibutamoren, an orally active, non-peptide growth hormone secretagogue developed by Merck as MK-0677 and L-163,191. Merck reported in 1995 that it raised growth hormone in dogs given it by mouth (Patchett et al., 1995).

It is an agonist of the growth hormone secretagogue receptor (GHS-R1a), whose natural ligand, the stomach hormone ghrelin, was identified in 1999 (Kojima et al., 1999).

That formula and weight match the ibutamoren free base in PubChem (CID 178024), the source of the CAS number, aliases and structure. A PubChem search for MK-677 returns the mesylate salt (CID 6450830), the form Merck's trial papers name (Sevigny et al., 2008).

Published work on MK-677 falls into six areas. Each summary below states the model used. Its many human trials appear as research history, with findings as the papers reported them.

Discovery as an oral, non-peptide secretagogue

Earlier growth hormone secretagogues, such as GHRP-6, were peptides. Merck's L-163,191 (MK-0677) released growth hormone from cultured rat pituitary cells with an EC50 of 1.3 nM, acted like GHRP-6 rather than growth hormone-releasing hormone (GHRH), and in dogs raised growth hormone without significant changes in aldosterone, LH, thyroxine or prolactin (Patchett et al., 1995). In beagles, oral MK-0677 raised peak growth hormone up to 15.8 fold, kept it elevated for up to 6 hours and raised IGF-I by about 30 percent (Jacks et al., 1996). Models: rat pituitary cells and dogs.

The ghrelin receptor

Merck scientists then cloned the target, a G protein-coupled receptor in pig and human pituitary and hypothalamus now called GHS-R1a, and proposed that the secretagogues mimic an undiscovered hormone (Howard et al., 1996). That hormone, ghrelin, was purified from rat stomach in 1999 as a 28-amino-acid peptide carrying an octanoyl group essential for activity (Kojima et al., 1999). Cryo-electron microscopy structures later showed how ghrelin and ibutamoren each sit in the human receptor's binding pocket (Liu et al., 2021). Models: cloned receptors, rat stomach extracts and purified receptor complexes.

Short-term human studies

In a placebo-controlled trial in 32 healthy adults aged 64 to 81, daily oral MK-677 raised mean 24-hour growth hormone by 97 percent after 2 weeks at the highest of three amounts tested; by 4 weeks IGF-I had reached the young-adult range and fasting glucose had risen (Chapman et al., 1996).

In eight volunteers on a calorie-restricted diet, mean daily nitrogen balance in a crossover week was 0.31 g with MK-677 against minus 1.48 g with placebo (Murphy et al., 1998). In 24 obese men over 8 weeks, fat-free mass rose, body fat did not change and glucose tolerance worsened (Svensson et al., 1998). Models: randomized human studies.

Year-long trials

The longest trial randomized 65 healthy adults aged 60 to 81 to MK-677 or placebo for two years. Growth hormone and IGF-I reached young-adult levels and fat-free mass rose 1.1 kg against a 0.5 kg fall on placebo, but visceral fat, total fat, strength and function did not differ. Fasting glucose rose, insulin sensitivity fell, and increased appetite, mild leg swelling and muscle pain were the most frequent side effects (Nass et al., 2008).

In 563 people with mild to moderate Alzheimer's disease, 12 months of MK-677 raised IGF-1 about 73 percent but did not slow progression (Sevigny et al., 2008). A phase IIb trial in 123 older adults after hip fracture was stopped early after a congestive heart failure signal in a few patients, and most functional measures did not differ from placebo (Adunsky et al., 2011). Models: randomized, placebo-controlled trials.

Animal models

In rats, oral MK-677 first raised peak growth hormone 1.8 fold. After six weeks, body growth and IGF-I had not increased, the response was gone and hypothalamic somatostatin expression had risen, which the authors linked to desensitization (Lee et al., 2018). In 5xFAD mice, a model of Alzheimer's-type amyloid pathology, MK-0677 increased hippocampal neurogenesis but did little to prevent amyloid deposition, synaptic loss or cognitive deficits, and mortality rose in mice that received 3 mg/kg (Tian et al., 2019). Models: rats and transgenic mice (animal data only).

Children with growth hormone deficiency

In 18 prepubertal children with idiopathic growth hormone deficiency, 7 to 8 days of oral ibutamoren mesylate raised peak growth hormone, IGF-I and IGFBP-3 in some children, with no change in prolactin, glucose, thyroid hormones or cortisol (Codner et al., 2001). Lumos Pharma later studied the compound as LUM-201. In 68 children in a growth hormone deficiency trial, the response to one oral challenge exceeded that to standard stimulation tests, with medians of 15.0 against 5.5 ng/mL; both authors consulted for the developer (Bright and Thorner, 2022). Models: pediatric clinical studies.