Ipamorelin: Molecular Structure

Molecular Structure and Properties#

Ipamorelin is a peptide whose molecular structure and properties have been characterized through analytical chemistry and structural biology studies.

Amino Acid Sequence#

Ipamorelin is a synthetic pentapeptide ghrelin receptor (GHS-R1a) agonist developed by Novo Nordisk. Its primary structure and analytical characteristics are well defined, enabling a detailed description of sequence, composition, and physicochemical behavior.

Primary structure and sequence

• Sequence (N→C): Aib–His–D-2-Nal–D-Phe–Lys–NH2. Aib = α-aminoisobutyric acid (2-amino-2‑methylpropanoic acid); D-2-Nal = D-2‑naphthylalanine; D-Phe = D‑phenylalanine; C-terminus is amidated (Lys‑NH2).
• One-letter style (with noncanonical and D-residues annotated): Aib–H–D-2Nal–D-F–K–NH2.
• Class: pentapeptide growth hormone secretagogue; synonym NNC 26‑0161.

Molecular formula and mass

• Molecular formula: C38H49N9O5.
• Molecular weight: ~711.9 Da (neutral molecule). High-resolution MS confirms [M+H]+ 712.3935 (theor.) and 712.3913 (exp.), [M+2H]2+ 356.7007 (theor.) and 356.7023 (exp.), and [M+3H]3+ 238.1364 (theor.) and 238.1371 (exp.). Predominant [M+2H]2+ at m/z 356.7001 is also observed in UHPLC-HRMS with characteristic b/y fragments including y1 at m/z 146.13 diagnostic for Lys at the C-terminus.

Isoelectric point, net charge, and charge distribution

• Ionizable groups: free N-terminus (pKa ~7.7–8.0), His imidazole (pKa ~6.0), Lys ε-amine (pKa ~10.5); C-terminus is amidated (non-ionizable). Aromatic D-2‑Nal and D‑Phe, and Aib are non-ionizable.
• Net charge at pH 7.4: approximately +2. The Lys side chain is protonated (+1), the N-terminus largely protonated (+1), and His is mostly neutral at pH 7.4.
• Estimated isoelectric point (pI): approximately 10–10.5, dominated by the Lys ε-amine; no explicit experimental pI was reported in the retrieved sources. This estimate follows standard residue pKa values given the amidated C-terminus and basic side chains.
• Charge distribution: positive charge density is concentrated at the N-terminus and the Lys ε-amine; the central residues are hydrophobic/aromatic, and His can contribute weakly positive charge near neutrality depending on microenvironment.

Structural and conformational features

• Noncanonical Aib at the N-terminus is known to restrict backbone conformations and favor helical/turn propensities in short peptides, enhancing proteolytic stability; ipamorelin belongs to the GHS pentapeptide series employing Aib for conformational bias (medicinal chemistry SAR context).
• Two central D-aromatic residues (D‑2‑naphthylalanine and D‑phenylalanine) provide a bulky hydrophobic/aromatic cluster important for high-affinity engagement of the lipophilic pocket in GHS‑R1a; mass spectral fragments and SAR literature are consistent with this aromatic core.
• C-terminal Lys‑NH2 contributes a basic handle and is characteristic of potent pentapeptidyl GHSs; MS/MS shows the diagnostic y1 ion for Lys consistent with C‑terminal lysinamide.

Analytical identifiers and synonyms

• Synonym: NNC 26‑0161; routes studied: IV/SC/intranasal; PK parameters are available but beyond scope of requested structural description.

Notes on evidence

• Sequence and C-terminal amidation are explicitly shown in MS-based doping-control analyses, with exact formula and high-resolution m/z values. Independent UHPLC‑HRMS work corroborates the doubly protonated species and Lys y1 fragment. Formula and mass also appear in a clinical pharmacology review. Where explicit pI is lacking, we report a reasoned estimate from ionizable groups as standard practice in peptide physicochemical analysis.

Stability and Formulation#

Ipamorelin is a pentapeptide growth hormone secretagogue (Aib–His–D-2-Nal–D-Phe–Lys–NH2) whose stability profile can be summarized across pH, temperature, likely degradation pathways, and formulation considerations as follows.

pH stability

• Aqueous mildly acidic conditions support stability. Medicinal chemistry reports on the ipamorelin lead series note “good stability even during prolonged storage in aqueous solution at pH 4–5,” which aligns with common practice for small therapeutic peptides (buffered, mildly acidic solutions).

Temperature sensitivity and matrix stability

• In biological matrices (urine) under analytical conditions, ipamorelin and related GHRPs showed no detectable degradation for up to 1 day at room temperature, 2 weeks at 4 °C, and 2 months at −20 °C, supporting short-term bench-top and longer cold storage stability in aqueous media (matrix-dependent).

Degradation pathways and chemical liabilities

• Strong-acid cleavage risk at the D-2-Nal–D-Phe junction. During synthesis/deprotection, anhydrous strong acid conditions (e.g., 50% TFA in dichloromethane at room temperature) caused cleavage between D-2-Nal and D-Phe; minimizing exposure time and rapid neutralization mitigated this. While this is a manufacturing-stage liability, it highlights susceptibility of this junction to acid-promoted backbone scission and informs avoidance of harsh acidic conditions in finished products.
• General peptide degradation expectations. Although ipamorelin-specific forced-degradation maps were not located in the retrieved texts, typical peptide pathways—amino-acid side-chain deamidation/isomerization (Asn/Gln; Asp) and oxidation (His, Met, Trp), backbone hydrolysis, and proteolysis—remain relevant. The sequence includes His and aromatic residues (2-Nal, Phe) that warrant control of oxidative and photolytic stress; proteolysis risk is reduced in vitro by using sterile, low-protease excipients and low temperatures. These expectations complement the empirical stability seen at pH 4–5 and under refrigerated/frozen storage.

Formulation considerations

• Aqueous vehicles: Preclinical dosing used sterile 0.9% sodium chloride injection as vehicle, demonstrating compatibility for parenteral administration; mildly acidic buffers (acetate/citrate, pH ~4–5) are consistent with observed stability and are commonly used for peptide products.
• Salt forms and excipients: Patent disclosures for GH secretagogues including ipamorelin list pharmaceutically acceptable acid-addition salts (e.g., acetate, citrate, trifluoroacetate, hydrochloride, among others) and conventional excipients for oral, nasal, and parenteral dosage forms. Selection of acetate or citrate salts/buffers at pH 4–5 is rational to enhance solubility and minimize hydrolysis/oxidation; avoid prolonged exposure to strong anhydrous acids.
• Storage/handling: Based on analytical matrix data, short bench-top exposure is acceptable, with preferred refrigerated storage for days to weeks and frozen storage for months when in aqueous solutions; lyophilization is a common strategy for peptides to minimize hydrolysis and oxidation during long-term storage, though ipamorelin-specific lyophile data were not directly retrieved here.

Key evidence summary

Evidence gaps

• We did not locate ipamorelin-specific forced-degradation studies delineating quantitative rates for oxidation/deamidation or exact Arrhenius temperature sensitivity; recommendations therefore rely on general peptide principles and indirect evidence from its lead series and matrix-stability studies.

Pharmacokinetics#

We summarize pharmacokinetic properties of ipamorelin (NNC 26-0161) across key ADME domains, emphasizing human data and noting route and species context.

Absorption

• Routes studied in humans include intravenous (IV), subcutaneous (SC), and intranasal (IN). Absolute bioavailability for SC or IN has not been reported in the sources retrieved here. Oral administration of growth hormone–releasing peptides (GHRPs), including ipamorelin, yields negligible systemic exposure; oral bioavailability is described as far below 1% in analytical/metabolism studies of this class, indicating that oral delivery is not viable without enabling technologies.

Distribution

• In humans following IV administration, the steady-state volume of distribution (Vdss) is approximately 0.22 L/kg, consistent with distribution largely confined to extracellular fluid and limited tissue binding.

Metabolism

• Ipamorelin undergoes peptide biotransformation typical of GHRPs. A principal pathway is C‑terminal deamidation; in comparative experiments, ipamorelin is susceptible to this pathway but appears less extensively deamidated than some analogues (e.g., GHRP‑2, hexarelin). In vitro human serum generates the main metabolites, with lower conversion than observed in vivo.

Elimination and excretion

• After IV dosing of GHRPs including ipamorelin, urinary recovery of both intact parent and metabolites indicates an important renal route of elimination. Analytical studies show rapid overall clearance of the class with little to no detectable analyte after 32–48 h post‑dose.

Half-life and clearance

• Human IV pharmacokinetics indicate an elimination half‑life of about 2 hours, systemic clearance of approximately 0.078 L/h/kg, and Vdss ~0.22 L/kg. These values are consistent across human studies summarized in the clinical pharmacology literature.

Bioavailability (quantitative)

• Absolute oral bioavailability is effectively negligible (far below 1%) based on metabolite/parent detection data across GHRPs; specific numeric absolute bioavailability for ipamorelin by SC or IN routes was not reported in the retrieved sources.

Key takeaways

• Ipamorelin exhibits short plasma persistence in humans (t1/2 ~2 h) with low Vd and modest systemic clearance, is metabolized primarily via peptide deamidation, and is eliminated with renal recovery of parent/metabolites. Oral dosing is not practical due to extremely low bioavailability; parenteral or intranasal routes have been explored clinically, though absolute bioavailability values for these routes were not reported in the sources identified.

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Related Reading#

• Ipamorelin overview and research guide
• Peptides similar to Ipamorelin
• Ipamorelin research evidence