Ipamorelin: Frequently Asked Research Questions

Introduction

Ipamorelin is a synthetic pentapeptide (five amino acids) with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 that was developed at Novo Nordisk and described by Raun and colleagues in 1998 as a selective growth hormone secretagogue [1]. It acts as an agonist at the growth hormone secretagogue receptor 1a (GHS-R1a), the receptor later shown to bind the stomach hormone ghrelin, and it is not an FDA-approved drug.

This article answers the questions most often asked about ipamorelin in search, in the order they are asked. Each answer is drawn from the primary literature or from public regulatory and trial-registry records, and each is attributed.

Key facts

• Ipamorelin is a pentapeptide, sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2, developed at Novo Nordisk A/S in Denmark and first published in 1998 [1].
• The developmental code name at Novo Nordisk was NNC 26-0161; the molecular formula is C38H49N9O5 and the molecular weight is approximately 711.9 daltons [1].
• Ipamorelin is an agonist of GHS-R1a, a receptor cloned by Howard and colleagues in 1996 [2], whose endogenous ligand ghrelin was identified by Kojima and colleagues in 1999 [3].
• In healthy male volunteers, Gobburu and colleagues reported a terminal half-life of about 2 hours for ipamorelin [4].
• Two phase 2 trials in postoperative ileus were sponsored by Helsinn Therapeutics (U.S.) and completed in 2009 and 2014 (NCT00672074, NCT01280344) [5, 6]; the first was published by Beck and colleagues in 2014 [7].
• Ipamorelin is not listed in Drugs@FDA as an approved drug or as the active ingredient of any approved product [8].
• Ipamorelin is not a GHRH analogue; CJC-1295 and sermorelin act at the GHRH receptor, ipamorelin does not [1, 9].

What is ipamorelin?

Ipamorelin is a synthetic five-residue peptide amide that Novo Nordisk chemists identified in a series of compounds lacking the central Ala-Trp dipeptide of growth hormone-releasing peptide 1 (GHRP-1) [1]. Its N-terminal residue is alpha-aminoisobutyric acid (Aib), followed by histidine, D-2-naphthylalanine, D-phenylalanine and a C-terminal lysine amide. Three of the five residues are non-natural, so the sequence has no counterpart in the human genome.

Raun and colleagues described the compound in the European Journal of Endocrinology in 1998 under the title "Ipamorelin, the first selective growth hormone secretagogue" [1]. The same Novo Nordisk group published a follow-on series of GHRPs derived from ipamorelin in the Journal of Medicinal Chemistry in 1998 [10]. The pharmaceutical name "ipamorelin" is used in the literature; the internal code was NNC 26-0161.

Ipamorelin is not a hormone found in the body, not a steroid, and not a growth hormone. It is a small synthetic peptide that binds a receptor whose natural ligand, ghrelin, was discovered a year after ipamorelin was published [3].

How does ipamorelin work?

Ipamorelin works as an agonist at GHS-R1a, the growth hormone secretagogue receptor. Howard and colleagues cloned this receptor from pituitary and hypothalamus in 1996 and showed it mediated the action of the synthetic GHRPs and the non-peptide secretagogue MK-0677 [2]. Kojima and colleagues then identified ghrelin, an acylated 28-amino-acid peptide from the stomach, as its endogenous ligand in 1999 [3].

In the 1998 discovery paper, Raun and colleagues reported that ipamorelin released growth hormone from primary rat pituitary cells with potency similar to GHRP-6, and that the response was blocked by a GHRP antagonist but not by a GHRH antagonist, placing the effect at a GHRP-type receptor [1]. In anesthetized rats and conscious swine, ipamorelin released growth hormone with potency comparable to GHRP-6 [1].

The selectivity finding was the paper's central point. In swine, GHRP-6 and GHRP-2 raised plasma ACTH and cortisol, whereas ipamorelin did not raise ACTH or cortisol to levels significantly different from those seen after GHRH, and this held at amounts more than 200-fold above the ED50 for growth hormone release [1].

Findings from research models do not establish safety or efficacy in humans. Sparta Labs makes no claims about the use of this compound.

Is ipamorelin FDA approved?

No. Ipamorelin is not approved by the U.S. Food and Drug Administration for any indication, and a search of Drugs@FDA returns no approved product containing it [8]. It is likewise not approved by the European Medicines Agency.

The compound did enter clinical development. Novo Nordisk sponsored early clinical pharmacology work in the 1990s, including the pharmacokinetic and pharmacodynamic study in healthy male volunteers reported by Gobburu and colleagues [4]. A decade later Helsinn Therapeutics (U.S.), Inc. sponsored two phase 2 trials of intravenous ipamorelin in postoperative ileus, registered as NCT00672074 (117 participants, completed December 2009) and NCT01280344 (320 participants, completed May 2014) [5, 6]. Neither trial was followed by a phase 3 program or a marketing application in the public record.

Ipamorelin is therefore supplied only as a research-use-only (RUO) reference material, a category the FDA distinguishes from products intended for human use [11]. Research-grade ipamorelin from Sparta Labs falls in that category.

What has ipamorelin been studied for?

Ipamorelin has been studied in pituitary cell culture, in rats and swine, in healthy human volunteers, and in one published phase 2 trial in surgical patients. The table below lists the principal published settings; they describe research questions, not approved uses.

Study	Year	Setting	What was reported
Raun et al. [1]	1998	Rat pituitary cells; rats; swine	GH release comparable to GHRP-6; no significant ACTH or cortisol rise in swine
Johansen et al. [12]	1999	Rats	Longitudinal bone growth after ipamorelin administration
Gobburu et al. [4]	1999	Healthy male volunteers, 5 infusion levels	Terminal half-life about 2 hours; single GH release episode peaking at 0.67 h
Venkova et al. [13]	2009	Rodent model of postoperative ileus	Gastrointestinal transit measures in the model
Beck et al. [7]	2014	Phase 2, 117 adults after bowel resection	Median time to tolerated meal 25.3 h vs 32.6 h placebo (p = 0.15)

Beck and colleagues described their trial as a multicenter, double-blind, placebo-controlled proof-of-concept study in which ipamorelin was given as intravenous infusions during the first postoperative week [7]. The difference in the primary endpoint did not reach statistical significance, and the authors noted the study was small.

Does ipamorelin increase testosterone?

The cited literature does not report a testosterone measurement for ipamorelin. Raun and colleagues assayed FSH, LH, prolactin and TSH in swine and reported that none of the secretagogues tested affected them; they also measured ACTH and cortisol and reported that ipamorelin did not raise either significantly [1]. Luteinizing hormone (LH) is the pituitary signal upstream of testosterone, and it was unaffected in that model.

Testosterone itself was not an endpoint in the Raun paper, the Gobburu volunteer study or the Beck trial [1, 4, 7]. No statement about ipamorelin and testosterone can be attributed to the primary literature on the compound.

How does ipamorelin differ from CJC-1295, sermorelin, GHRP-6 and hexarelin?

Ipamorelin, GHRP-6 and hexarelin belong to one pharmacological class, and CJC-1295 and sermorelin belong to another. The first group are growth hormone-releasing peptides acting at GHS-R1a; the second are analogues of growth hormone-releasing hormone (GHRH) acting at the GHRH receptor, a distinct class B G protein-coupled receptor [1, 2, 9, 14].

Compound	Class	Receptor	Length	Approval status
Ipamorelin	GHRP / GHS-R1a agonist	GHS-R1a	5 residues	Not approved
GHRP-6	GHRP / GHS-R1a agonist	GHS-R1a	6 residues	Not approved
Hexarelin	GHRP / GHS-R1a agonist	GHS-R1a	6 residues	Not approved
CJC-1295	GHRH analogue	GHRH receptor	29 residues plus DAC linker	Not approved
Sermorelin	GHRH analogue, GHRH(1-29)	GHRH receptor	29 residues	Formerly approved diagnostic (Geref), now discontinued

Within the GHRP group, the reported difference is hormone selectivity: Raun and colleagues found GHRP-6 and GHRP-2 raised ACTH and cortisol in swine and ipamorelin did not [1], and Massoud and colleagues reported that hexarelin raised cortisol and prolactin alongside growth hormone in humans [15]. Structural comparisons are set out in GHRP-6 vs ipamorelin.

Across the two groups the difference is the receptor. CJC-1295 is a tetrasubstituted GRF(1-29) analogue with an albumin-binding linker, as described by Jetté and colleagues in 2005 [9], and sermorelin is GHRH(1-29) itself [14]. Both are compared with ipamorelin in CJC-1295 vs ipamorelin and sermorelin vs ipamorelin, and the class distinction is explained in growth hormone secretagogues vs GHRH analogues.

Why is ipamorelin so often paired with CJC-1295 in search?

Ipamorelin and CJC-1295 appear together in search because they act at two different receptors on the same pituitary cell type. A body of literature dating to Bowers and colleagues in 1990 reported that a GHRP and GHRH given in the same study produced synergistic growth hormone release in humans [16]. That literature concerns GHRP-6 and GHRH, not the specific pair searched for.

The companion article CJC-1295 and ipamorelin explained reviews that literature in detail. Sparta Labs supplies the two compounds separately as research-use-only reference materials; this library describes the published literature and does not describe any procedure for combining them.

Where does research-grade ipamorelin come from?

Research-grade ipamorelin is made by solid-phase peptide synthesis (SPPS), the resin-based method introduced by Merrifield in 1963 [17], followed by cleavage, purification by reversed-phase high-performance liquid chromatography (HPLC) and lyophilization. Identity is confirmed by mass spectrometry against the expected molecular weight of about 711.9 daltons, and chromatographic purity is reported on a certificate of analysis (COA).

Sparta Labs catalogs ipamorelin with per-batch analytical documentation, and the ipamorelin sourcing and quality article explains what the COA reports and how to read it. The material is a laboratory reagent, not a pharmaceutical product, and is not the same article as any investigational drug substance used in the trials cited above.

Summary

Ipamorelin is a synthetic pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, published by Raun and colleagues at Novo Nordisk in 1998 as a growth hormone secretagogue acting at GHS-R1a, the ghrelin receptor. In rats and swine the authors reported growth hormone release comparable to GHRP-6 without the ACTH and cortisol rise seen with GHRP-6; testosterone was not measured. Human data comprise a volunteer study reporting a 2-hour half-life and two completed phase 2 trials, neither followed by approval. Ipamorelin is not FDA approved, is a different class from CJC-1295 and sermorelin, and is supplied only as a research-use-only reference material.

References

1. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-561. PMID: 9849822. DOI: 10.1530/eje.0.1390552
2. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974-977. PMID: 8688086. DOI: 10.1126/science.273.5277.974
3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660. PMID: 10604470. DOI: 10.1038/45230
4. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999;16(9):1412-1416. PMID: 10496658. DOI: 10.1023/a:1018955126402
5. Helsinn Therapeutics (U.S.), Inc. Safety and Efficacy of Ipamorelin for Management of Post-Operative Ileus. ClinicalTrials.gov identifier NCT00672074. Phase 2, 117 participants, completed December 2009. ClinicalTrials.gov record
6. Helsinn Therapeutics (U.S.), Inc. Safety and Efficacy of Ipamorelin Compared to Placebo for the Recovery of Gastrointestinal Function. ClinicalTrials.gov identifier NCT01280344. Phase 2, 320 participants, completed May 2014. ClinicalTrials.gov record
7. Beck DE, Sweeney WB, McCarter MD; Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-1534. PMID: 25331030. DOI: 10.1007/s00384-014-2030-8
8. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs (database). Source: accessdata.fda.gov
9. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052-3058. PMID: 15817669. DOI: 10.1210/en.2004-1286
10. Ankersen M, Johansen NL, Madsen K, Hansen BS, Raun K, Nielsen KK, et al. A new series of highly potent growth hormone-releasing peptides derived from ipamorelin. J Med Chem. 1998;41(19):3699-3704. PMID: 9733495. DOI: 10.1021/jm9801962
11. U.S. Food and Drug Administration. Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Guidance for Industry and Food and Drug Administration Staff. November 2013. Source: fda.gov
12. Johansen PB, Nowak J, Skjaerbaek C, Flyvbjerg A, Andreassen TT, Wilken M, et al. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. 1999;9(2):106-113. PMID: 10373343. DOI: 10.1054/ghir.1999.9998
13. Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. J Pharmacol Exp Ther. 2009;329(3):1110-1116. PMID: 19289567. DOI: 10.1124/jpet.108.149211
14. Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs. 1999;12(2):139-157. PMID: 18031173. DOI: 10.2165/00063030-199912020-00007
15. Massoud AF, Hindmarsh PC, Brook CG. Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study. J Clin Endocrinol Metab. 1996;81(12):4338-4341. PMID: 8954038. DOI: 10.1210/jcem.81.12.8954038
16. Bowers CY, Reynolds GA, Durham D, Barrera CM, Pezzoli SS, Thorner MO. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 1990;70(4):975-982. PMID: 2108187. DOI: 10.1210/jcem-70-4-975
17. Merrifield RB. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J Am Chem Soc. 1963;85(14):2149-2154. DOI: 10.1021/ja00897a025