Ibutamoren (MK-677): Molecular Structure

Molecular Structure and Properties#

Ibutamoren (MK-677) is not a peptide but rather a non-peptide small molecule growth hormone secretagogue. It belongs to the spiroindoline sulfonamide chemical class. With a molecular weight of 528.67 Da, molecular formula C27H36N4O5S, and CAS number 159634-47-6, ibutamoren was designed through medicinal chemistry optimization at Merck Research Laboratories to create an orally bioavailable ghrelin mimetic.

The compound is typically formulated as ibutamoren mesylate (the methanesulfonate salt) for improved aqueous solubility and stability, with CAS number 159752-10-0 for the salt form.

Chemical Structure#

Unlike peptide-based growth hormone secretagogues (such as GHRP-6, GHRP-2, or hexarelin), ibutamoren is a synthetic small molecule. Its key structural features include:

• Spiroindoline core: A rigid bicyclic ring system that provides the structural scaffold for receptor binding
• Sulfonamide group: Essential for binding affinity at the GHS-R1a receptor
• Benzyl substituents: Contribute to hydrophobic interactions within the receptor binding pocket
• Amino acid-derived elements: The molecule incorporates structural elements derived from tryptophan, contributing to its ghrelin-mimetic properties

Receptor Binding and Pharmacology#

Ibutamoren binds selectively to the growth hormone secretagogue receptor type 1a (GHS-R1a), the same receptor activated by endogenous ghrelin. Key pharmacological properties:

• GHS-R1a agonism: High-affinity binding with EC50 in the low nanomolar range
• Selectivity: Does not significantly interact with other G-protein coupled receptors at therapeutic concentrations
• Functional mimicry: Activates the same intracellular signaling cascades as ghrelin, including Gq/11-mediated calcium mobilization and phospholipase C activation
• No GH receptor activity: Acts upstream of GH release; does not directly activate the GH receptor

Physicochemical Properties#

• Solubility: The free base has moderate aqueous solubility; the mesylate salt form substantially improves water solubility
• Stability: Stable as a solid under standard storage conditions
• Oral absorption: Well absorbed from the gastrointestinal tract, a key advantage over peptide-based GH secretagogues that require parenteral administration

Pharmacokinetics#

Ibutamoren exhibits favorable oral pharmacokinetics that support once-daily dosing despite its relatively short plasma half-life.

Absorption: Rapidly absorbed after oral administration, with peak plasma concentrations achieved within 1-2 hours. Food does not significantly affect bioavailability.

Distribution: Distributes widely into tissues. Protein binding has not been fully characterized in published literature.

Metabolism: Metabolized hepatically, primarily through oxidative pathways. Specific CYP enzyme involvement has not been fully delineated in public domain literature.

Elimination: The plasma half-life is approximately 4-6 hours. However, the functional duration of GH and IGF-1 elevation extends to approximately 24 hours, supporting once-daily dosing. This extended functional duration results from the sustained downstream effects on the GH-IGF-1 axis rather than from drug persistence.

Structural Comparison with Related Compounds#

Ibutamoren is structurally and mechanistically distinct from both peptide GH secretagogues and recombinant GH:

• vs. Ghrelin (endogenous): Ghrelin is a 28-amino-acid peptide with an octanoyl modification at Ser3, with a plasma half-life of only 10-30 minutes. Ibutamoren mimics ghrelin's receptor activity but as a small molecule with oral bioavailability and much longer duration of action.
• vs. GHRP-6/GHRP-2: These are synthetic hexapeptide GH secretagogues that also activate GHS-R1a but require subcutaneous or intravenous administration due to peptide degradation in the GI tract. Ibutamoren's non-peptide structure overcomes this limitation.
• vs. Recombinant GH (somatropin): Somatropin directly replaces GH via daily injection. Ibutamoren stimulates endogenous GH release, preserving pulsatile secretion patterns but producing lower absolute GH levels.
• vs. GHRH analogs (sermorelin, tesamorelin): These act through the GHRH receptor, a different mechanism from GHS-R1a activation. The two pathways are synergistic, and combined GHRH + GHS stimulation produces greater GH release than either alone.

Related Reading#

• Ibutamoren (MK-677) overview and research guide
• Peptides similar to Ibutamoren (MK-677)
• Ibutamoren (MK-677) research evidence