Research Dossier on Ipamorelin

(Growth Hormone Secretagogue)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Ipamorelin is a synthetic pentapeptide ghrelin mimetic that activates the growth-hormone secretagogue receptor type 1a (GHSR1a). The sequence is commonly reported as Aib–His–D-2-Nal–D-Phe–Lys-NH₂, where Aib denotes α-aminoisobutyric acid and D-2-Nal denotes D-2-naphthylalanine. These non-canonical residues and D-configurations contribute to receptor selectivity and metabolic stability in vitro and in vivo.

Biophysical and medicinal-chemistry work during ipamorelin’s discovery optimized for high potency at GHSR1a, robust GH release, and minimal off-target pituitary effects (e.g., ACTH, cortisol, prolactin) compared with first-generation GHRPs. In animal and cellular assays, ipamorelin shows GHRP-like receptor pharmacology with GH-releasing potency similar to classical hexapeptides, despite being a pentapeptide scaffold.

Discovery history (lab, year, species)

Ipamorelin was characterized in the late 1990s by researchers at Novo Nordisk and collaborators, who published its pharmacology and selectivity profile in 1998 (European Journal of Endocrinology). Early work reported dose-responsive GH release in rodents and swine and highlighted a lack of ACTH/cortisol co-stimulation even at exposures far above the GH ED₅₀.

Endogenous vs synthetic origin

• Synthetic: Ipamorelin is a fully synthetic ghrelin-receptor agonist.

• Endogenous system targeted: The ghrelin–GHSR1a axis (a GPCR signaling system) regulates GH secretion and GI motility, among other processes. Ghrelin is the endogenous acylated peptide ligand for GHSR1a; ipamorelin mimics ghrelin’s somatotrophic action with comparatively selective endocrine output in early studies.

Homologs, analogs, derivatives

• GHSR agonist class: GHRP-2, GHRP-6, hexarelin, relamorelin (macimorelin for diagnostic use), and other peptidomimetics with varying selectivity for GH vs ACTH/prolactin.

• GHRH/GHRHR agonists: Sermorelin, tesamorelin—distinct pathway (GHRH receptor), often synergistic with GHSR agonists in human physiology studies but pharmacodynamically different from ipamorelin. (Synergy is a class observation; not specific to ipamorelin.)

Historical Development & Research Trajectory

Key milestones in discovery and study

• 1998 (Raun et al.): First full pharmacologic description—pentapeptide, selective GH release in rats and swine; no measurable ACTH/cortisol rise even at >200× the GH ED₅₀ (species- and design-specific).

• 1999 (Gobburu et al.): Human PK/PD modeling in healthy volunteers with 15-min IV infusions across five dose levels; short systemic t½ ~2 h, Vss ~0.22 L·kg⁻¹, CL ~0.078 L·h⁻¹·kg⁻¹; single GH pulse peaking at ~0.67 h post-dose.

• 2010s: Exploration of GHSR agonists for post-operative ileus (POI) and GI dysmotility. Phase 2 RCT of ipamorelin in bowel-resection patients showed acceptable short-term safety but no significant primary-endpoint efficacy versus placebo. (See Clinical section.)

Paradigm shifts and controversies

1. Selectivity vs. dose-dependent pleiotropy. Although ipamorelin demonstrated minimal ACTH/cortisol effects in preclinical systems and early profiles, later ghrelin system reviews emphasize that high systemic exposure to ghrelin/GHSR agonists can evoke ACTH, cortisol, and prolactin in humans—highlighting the context-dependence of endocrine selectivity across the class.

2. From endocrine to GI motility. Beyond somatotroph biology, ghrelin receptor agonists were investigated for prokinetic effects. Ipamorelin’s Phase 2 RCT in POI did not meet its primary efficacy endpoint, tempering clinical enthusiasm for this particular compound in that indication (other ghrelin agonists pursued GI indications separately).

3. Clinical evidence gap. As of September 26, 2025, no completed, positive late-phase trials establish therapeutic efficacy for ipamorelin; registered studies exist (Phase 2) without confirmatory Phase 3 success. (See registry listings below.)

Evolution of scientific interest

Ipamorelin remains a reference-grade GHSR1a agonist in endocrine physiology (GH pulsatility, synergy with GHRH) and a prokinetic candidate explored in POI. The broader field pivoted toward newer agonists (e.g., relamorelin) and toward leveraging GHSR biology in metabolic, GI, and CNS contexts—areas where dose–exposure–selectivity trade-offs remain central.

Mechanisms of Action

Primary and secondary receptor interactions

• Primary target: GHSR1a (growth-hormone secretagogue receptor type 1a), a class A GPCR. Ipamorelin acts as an agonist, stimulating GH release from anterior-pituitary somatotrophs.

• Selectivity: In comparative animal work, ipamorelin did not elevate ACTH/cortisol to a measurable degree even at high exposures, unlike some GHSR agonists (e.g., GHRP-6, GHRP-2). However, class-level literature cautions that supraphysiologic GHSR activation (via ghrelin or other agonists) can, in humans, increase ACTH, cortisol, and prolactin, especially at high doses. Ipamorelin-specific high-dose human endocrine data remain limited.

Intracellular signaling pathways

GHSR1a couples primarily to Gq/11→PLCβ→IP₃/Ca²⁺ signaling in somatotrophs, facilitating GH granule exocytosis. Additional coupling to Gi/o and β-arrestin-mediated pathways has been described for ghrelin/GHSR, with cell-type-dependent signaling bias. The endocrine output is episodic: ipamorelin evokes a single GH pulse temporally linked to exposure and rapidly waning once infusion stops, as captured in human PK/PD modeling.

CNS vs peripheral effects

• Peripheral (pituitary): Primary, via somatotroph GHSR1a activation and GH secretion.

• CNS: GHSR1a is widely expressed in hypothalamic circuits regulating appetite, stress, and autonomic output. Direct brain delivery of ipamorelin under intact BBB conditions has Not established evidence; CNS behavioral effects summarized in ghrelin reviews pertain mainly to endogenous ghrelin or other agonists.

Hormonal, metabolic, immune interactions

• Somatotropic axis: Ipamorelin-induced GH pulses are followed by IGF-1 changes via hepatic signaling; quantitative IGF-1 outcomes for ipamorelin in controlled human trials are limited. Class-wide effects on glucose/insulin sensitivity are context-dependent and influenced by dose, timing, and subject phenotype (Not established for ipamorelin-specific long-term studies).

Evidence grading (A–C)

• A (replicated core biology): GHSR1a agonism → GH pulse generation; ipamorelin’s selective GH release in preclinical profiling; human PK/PD capturing t½ ~2 h and single-pulse GH kinetics after short infusions.

• B (translational/indication-level): Prokinetic rationale in POI—Phase 2 safety acceptable but no primary efficacy; human endocrine selectivity at very high exposures remains data-limited.

• C (hypothesis/early): CNS applications (mood/stress), long-term metabolic modulation, and disease-specific benefits remain investigational for this molecule.

Pharmacokinetics & Stability

ADME profile (humans and animals)

• Absorption: Human PK/PD data derive from 15-min IV infusions in healthy men with dose-proportional PK over 4.21–140.45 nmol·kg⁻¹ (investigational doses used in study Gobburu 1999). Oral or transdermal PK is Not established for clinical-grade ipamorelin; nasal and non-IV routes have preclinical documentation.

• Distribution: Vss ~0.22 L·kg⁻¹ indicates confinement near extracellular fluid volumes—typical for small peptides with limited tissue partitioning.

• Metabolism/clearance: t½ ~2 h, CL ~0.078 L·h⁻¹·kg⁻¹ in healthy men; elimination consistent with peptide catabolism and limited distribution.

• Excretion: Specific human metabolite maps and excretion fractions are Not established.

Plasma half-life & degradation pathways

Short systemic persistence (~2 h) complements the single-pulse GH PD: GH peaks ~0.67 h post-infusion and declines exponentially thereafter across all doses in that study design. (Different routes/regimens may alter timing; sustained infusion can attenuate responsiveness via somatotroph desensitization/brake phenomena described for the class.)

Stability in vitro & in vivo

• In vitro: The pentapeptide design with D-residues/non-canonical amino acids supports enhanced protease resistance vs canonical sequences (class-level rationale). Comparative in-vitro stability across media and temperatures is model-dependent and Not standardized across labs.

• In vivo: The human t½ ~2 h indicates maintained short-acting behavior despite stability optimizations—useful for episodic GH stimulation paradigms.

Storage/reconstitution considerations

Peer-reviewed literature does not provide validated, product-agnostic reconstitution/shelf-life curves for research vials; standard peptide handling applies (cold chain, protect from light, minimize freeze–thaw). Lot-specific stability data are vendor-dependent (outside the scope of peer-review).

Preclinical Evidence

Animal and in vitro studies

Endocrine selectivity and GH potency.

• In primary rat pituitary cells and anesthetized rats, ipamorelin released GH with potency/efficacy similar to GHRP-6. In conscious swine, ipamorelin’s GH ED₅₀ was ~2.3 nmol·kg⁻¹, again comparable to GHRP-6. Crucially, ipamorelin did not raise ACTH/cortisol above GHRH-like levels, even at exposures >200× the GH ED₅₀—species- and context-specific observations that seeded its “selective secretagogue” designation. (Investigational animal doses used in study Raun 1998.)

Comparative pharmacology within the GHS class.

• Multiple GHSs (GHRP-2, GHRP-6, hexarelin) demonstrate co-stimulation of ACTH/cortisol in certain settings, whereas ipamorelin’s profile was designed to minimize these effects in preclinical systems. Later human reviews show dose-dependent endocrine pleiotropy for ghrelin/GHSR agonists generally, underlining that selectivity is not absolute at high exposures.

Nasal/alternate-route pharmacokinetics (preclinical).

• In male rats, ipamorelin displayed lower systemic clearance than some comparator GHRPs and was evaluated for intranasal absorption, offering exploratory non-IV route data (preclinical only). (Investigational preclinical PK in Johansen 1998/Xenobiotica.)

Dose ranges tested (investigational; illustrative)

• Rodents/swine (endocrine): nmol·kg⁻¹ ranges for GH release; ED₅₀ ~2.3 nmol·kg⁻¹ in swine (conscious). (Investigational doses used in Raun 1998.)

• Rats (PK/absorption): IV bolus and intranasal ranges per Xenobiotica report, with notable inter-peptide clearance differences. (Investigational doses used in Johansen 1998.)

Comparative efficacy/safety

Across preclinical endocrine paradigms, ipamorelin reliably triggers GH pulses with attenuated ACTH/cortisolreadouts relative to several legacy GHSs under matched conditions. No GLP-style, long-term toxicology program focused solely on ipamorelin was identified in the public domain (Not established).

Principal limitations

• Species differences and anesthesia/handling can alter pituitary responsiveness and adrenal readouts.

• Comparative studies vary in route (IV vs SC vs intranasal), dose magnitude, and stress context—limiting cross-study pooling.

Human Clinical Evidence

Summary: Human data include PK/PD in healthy volunteers (short IV infusions) and Phase 2 proof-of-concept studies for post-operative ileus. As of the stated date, no successful Phase 3 outcomes for ipamorelin are published; no approved therapeutic indications exist.

Phase I (PK/PD in healthy volunteers)

• Design (Gobburu 1999): 5 cohorts, 15-min IV infusion at 4.21, 14.02, 42.13, 84.27, 140.45 nmol·kg⁻¹(investigational doses used in study Gobburu 1999).

• PK: t½ ~2 h, CL ~0.078 L·h⁻¹·kg⁻¹, Vss ~0.22 L·kg⁻¹; dose proportionality observed.

• PD: Single episode GH release peaking ~0.67 h post-start of infusion, waning quickly thereafter; indirect-response modeling fit the episodic pattern across all doses.

Phase II (post-operative ileus, POI)

• Study (Beck 2014; NCT00672074): Prospective, randomized, controlled Phase 2 trial of ipamorelin in patients after bowel resection with primary anastomosis.

• Findings: Good short-term safety but no statistically significant improvement vs placebo on the trial’s primary efficacy endpoint for GI recovery (details in publication). (Investigational regimen used in study Beck 2014).

• Registry (NCT01280344): A Phase 2 dose-finding study planned to evaluate recovery of GI function post-resection; registry provides design snapshots. (Interventional trial record; outcomes not establishing efficacy.)

Safety signals/adverse events (human studies)

• Phase I PK/PD: No severe safety signals in the brief IV-infusion study; tolerability acceptable under controlled conditions. Long-term safety, immunogenicity, and drug–drug interaction data are Not established.

• Phase II POI: Ipamorelin was well tolerated in the randomized study, but failed to improve the primary clinical outcome.

ClinicalTrials.gov IDs

• NCT00672074 — Phase 2, ipamorelin vs placebo for POI (sponsor-identified, published results summarized above).

• NCT01280344 — Phase 2 dose-finding, ipamorelin for GI recovery after bowel resection (registry snapshot).

Comparative Context

Related peptides

• GHSR agonists: GHRP-2/6 (older generation), relamorelin (developed for gastroparesis/ileus), macimorelin (oral diagnostic for adult GH deficiency). These share receptor targeting but differ in selectivity, PK, and clinical trajectories.

• GHRH agonists: Sermorelin/tesamorelin act upstream via GHRH receptor, often producing synergistic GH pulsatility with GHSR agonists in physiology studies; mechanisms and PK are distinct.

Advantages (research perspective)

• Short-acting, pulse-like GH stimulation with well-characterized human PK/PD from the 1999 model.

• Preclinical selectivity for GH over ACTH/cortisol/PRL distinguishes ipamorelin from many GHSR agonists—within specific dose ranges and contexts.

Disadvantages / constraints

• Clinical efficacy for GI dysmotility: not demonstrated in Phase 2.

• Dose-exposure dependency of class-level endocrine selectivity (ACTH/cortisol/PRL can rise at high exposures with ghrelin/GHSR agonists). Ipamorelin-specific high-dose human endocrine data are sparse.

Research category placement

• GHSR1a agonist used to probe GH pulsatility, axis synergy, and GI motility hypotheses; tool compound for endocrine and GI translational research (without established therapeutic indication).

Research Highlights

• Selective GH secretagogue: Animal and ex vivo data show robust GH release with minimal ACTH/cortisolchanges—even at very high exposures relative to the GH ED₅₀. (Species/context caveats apply.)

• Quantified human PK/PD: Short IV infusions yield t½ ~2 h, Vss ~0.22 L·kg⁻¹, CL ~0.078 L·h⁻¹·kg⁻¹, with a single GH peak at ~0.67 h; PD captured by an indirect-response model.

• POI translation: Phase 2 RCT in bowel-resection patients showed safety but no significant primary outcome benefit; underscores the complexity of applying GHSR agonism to post-surgical GI recovery.

Conflicting/uncertain areas

• High-dose endocrine selectivity in humans: the ghrelin/GHSR literature documents ACTH/cortisol/PRL rises at high exposures for the class; ipamorelin-specific confirmation in modern human dose ranges is Not established.

• CNS outcomes: robust ipamorelin-specific CNS efficacy data are lacking; BBB crossing under physiologic conditions is Not established.

Potential Research Applications (no clinical claims; research-use framing)

1. Endocrine physiology of GH pulsatility

   • Use ipamorelin to elicit single GH pulses under controlled timing, compare with GHRH agonists, and quantify synergy and somatostatin brake dynamics via high-frequency sampling and deconvolution. (Human synergy is class-documented; ipamorelin-specific synergy datasets are comparatively modest.)

2. Modeling dose–exposure–selectivity

   • Map GH vs ACTH/cortisol/PRL responses across exposure ranges in translational models to define selectivity envelopes, using PD endpoints and population PK/PD methods validated in 1999.

3. GI motility mechanisms

   • Investigate enteric neural and smooth-muscle effects of GHSR activation ex vivo and in vivo; integrate ipamorelin with manometry and transit measures to refine mechanistic (not efficacy) hypotheses for POIand related dysmotility states.

4. Receptor-signaling bias

   • Profile Gq vs Gi signaling and β-arrestin recruitment by ipamorelin relative to other agonists; link to gene-expression changes and secretory phenotypes in somatotroph and GI cell models.

5. Bioprocess/assay standardization

   • Use ipamorelin as a calibrator in GH-release assays or to maintain somatotroph viability in vitro under low-serum conditions, while documenting batch-specific potency and stability (research-only use).

Safety & Toxicology

Preclinical toxicity data

Dedicated GLP repeat-dose, genotoxicity, reproductive, and carcinogenicity packages focused specifically on ipamorelin are not publicly available. Class-wide concerns relate to endocrine pleiotropy at high exposures and theoretical pro-mitogenic signaling via GH/IGF-1 axes; these are mechanistic considerations rather than ipamorelin-specific clinical findings. (Not established for ipamorelin itself.)

Known/theoretical molecular risks

• Endocrine cross-stimulation at high exposure (ACTH/cortisol/PRL) is documented for ghrelin/GHSR agonistsbroadly; ipamorelin was designed to minimize this, but human high-dose data are limited.

• Axis effects: Repeated large-magnitude GH pulses could influence IGF-1 and downstream pathways; chronic-exposure safety for ipamorelin is Not established.

• Immunogenicity: As a small peptide with non-canonical residues, immunogenic risk is unknown without formal studies (Not established).

Human safety observations

• Healthy-volunteer PK/PD: short-term infusions were well tolerated; no severe acute safety signals were reported in that trial setting.

• POI Phase 2: Acceptable short-term safety; no primary-endpoint benefit. Long-term safety and drug–drug interaction profiles remain Not established.

Data gaps

• Chronic exposure safety, comprehensive immunogenicity, organ-system surveillance, and drug–drug interaction data are Not established for ipamorelin.

Limitations & Controversies

• Clinical efficacy not established: Despite mechanistic rationale for POI, ipamorelin did not meet primary endpoints in a Phase 2 RCT; there is no successful Phase 3 dataset or approved use for this molecule.

• Selectivity depends on exposure: While preclinical work shows minimal ACTH/cortisol effects for ipamorelin, class reviews highlight dose-dependent endocrine pleiotropy with ghrelin agonists; robust, modern human high-dose selectivity data for ipamorelin are lacking.

• CNS claims: Ipamorelin-specific CNS outcomes are not established; extrapolations from ghrelin should be treated as hypothesis-generating only.

Future Directions

• Exposure–response mapping (human physiology)
  Establish dose–exposure–selectivity relationships in controlled human physiology studies (GH vs ACTH/cortisol/PRL), using frequent sampling, deconvolution, and indirect-response models to define safe/selective GH-pulse envelopes.

• Mechanistic GI endpoints
  Apply motility mapping (scintigraphy, manometry) and enteric network analyses to parse where GHSR agonism aids vs fails in post-surgical dysmotility; compare ipamorelin with other agonists under matched designs.

• Receptor-signaling bias & medicinal chemistry
  Dissect Gq/Gi/β-arrestin profiles and design derivatives tuned for desired tissue outputs (somatotroph vs enteric vs CNS) while preserving endocrine selectivity.

• Safety maturation
  If pursued, conduct GLP repeat-dose and immunogenicity studies and assemble comprehensive PK/PD, DDI, and long-term safety packages to inform any future translational work.

References

1. Raun K, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–561. doi:10.1530/eje.0.1390552. PMID: 9849822. (Selective GH release; minimal ACTH/cortisol in animal models.)

2. Gobburu JVS, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-Pharmacodynamic Modeling of Ipamorelin in Human Volunteers. Pharm Res. 1999;16:1412–1416. doi:10.1023/A:1018955126402. (t½ ~2 h; Vss ~0.22 L·kg⁻¹; CL ~0.078 L·h⁻¹·kg⁻¹; GH peak ~0.67 h.)

3. Beck DE, et al. Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus. Int J Colorectal Dis. 2014;29(12):1527–1534. doi:10.1007/s00384-014-2002-2. (Phase 2 POI; safety acceptable; no primary-endpoint benefit.)

4. ClinicalTrials.gov. NCT00672074 — Safety and Efficacy of Ipamorelin for Management of Post-operative Ileus.(Registry record; Phase 2.)

5. ClinicalTrials.gov. NCT01280344 — Safety and Efficacy of Ipamorelin Compared to Placebo for Recovery of GI Function after Bowel Resection. (Registry snapshot; Phase 2 dose finding.)

6. Müller TD, et al. Ghrelin. Mol Metab/PMC Review. 2015; comprehensive mechanistic overview of ghrelin/GHSR biology; dose-dependent endocrine effects at high exposures.

7. Veldhuis JD, et al. Integrating Growth Hormone Secretagogues into the Ghrelin System. Int J Endocrinol.2010:879503. (Class-level endocrine pleiotropy at high exposures; physiology context.)

8. Kojima M, et al. Ghrelin: Structure and Function. Physiol Rev. 2005;85:495–522. (Endogenous ligand; GHSR1a GPCR signaling.)

9. Johansen PB, et al. Pharmacokinetic evaluation of ipamorelin and other peptidyl GHS with emphasis on nasal absorption (rat). Xenobiotica. 1998;28:1083–1092. (Preclinical PK; intranasal/IV routes.)

10. Mosińska P, et al. Role of Relamorelin and Other Ghrelin Receptor Agonists in GI Disorders. J Neurogastroenterol Motil. 2017;23:171–179. (GhRELIN agonists in GI; context for ipamorelin development.)

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.