Ipamorelin

This landmark paper from Novo Nordisk describes the design, synthesis, and pharmacological characterization of ipamorelin, a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) identified within a series of compounds lacking the central Ala-Trp dipeptide of growth hormone-releasing peptide (GHRP)-1. In primary rat pituitary cell cultures, ipamorelin released growth hormone with potency and efficacy comparable to GHRP-6. In anesthetized swine, intravenous administration produced a dose-dependent rise in plasma growth hormone. Critically, the authors reported that ipamorelin did not elevate ACTH or cortisol above baseline at doses more than 200-fold above the ED50 for growth hormone release — a selectivity profile distinct from earlier GHRPs such as GHRP-6 and hexarelin. Prolactin release was likewise not significantly stimulated, framing ipamorelin as the first GHRP-receptor agonist with this clean secretory profile.

Researchers at Novo Nordisk designed a small five-amino-acid peptide and tested how it triggers growth hormone release. In both isolated pituitary cells and live pigs, ipamorelin released growth hormone just as strongly as earlier compounds in its class. The key finding was what it did not do: it did not raise cortisol, ACTH, or prolactin — three hormones that other peptides in this family tend to push up as an unwanted side effect. This selectivity is the reason ipamorelin became a reference point for studying growth hormone biology without the noise of other hormonal changes.

This early-phase human pharmacology study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin in healthy male volunteers. Subjects received one of five infusion rates (4.21, 14.02, 42.13, 84.27, or 140.45 nmol/kg over 15 minutes), with eight volunteers per dose level. Pharmacokinetic parameters were dose-proportional: a terminal half-life of approximately 2 hours, clearance of 0.078 L/h/kg, and a steady-state volume of distribution of 0.22 L/kg. The growth hormone response followed a single episodic pulse peaking at roughly 0.67 hours post-infusion with an exponential decline back to baseline at all dose levels. The ipamorelin-to-GH concentration relationship was modeled using a population indirect response framework, providing one of the first quantitative descriptions of GH pulsatility under a GHS-R1a agonist in humans.

Researchers gave ipamorelin to healthy adult volunteers at five different doses and tracked how the peptide moved through the body and how growth hormone responded. Ipamorelin cleared from circulation with a half-life of about two hours, and growth hormone rose in a single pulse roughly 40 minutes after dosing before returning to baseline. The behavior was predictable across doses, which let the researchers build a mathematical model linking ipamorelin levels to growth hormone output. This kind of model is what later studies use to plan dosing and timing in animal and translational research.