Ipamorelin, the first selective growth hormone secretagogue

This 1998 paper from the Novo Nordisk medicinal chemistry group is the foundational pharmacology paper for Ipamorelin and the document that established the selectivity story underlying the entire selective-GH-secretagogue class. The team designed a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) and characterized its potency at the growth-hormone-secretagogue receptor across in vitro and in vivo assays. Ipamorelin produced GH release with potency comparable to GHRH itself in cultured pituitary cells, and triggered dose-dependent GH elevation in rats and swine. The defining finding was selectivity: across the same dose ranges that produced robust GH release, the peptide did not significantly elevate ACTH, cortisol, prolactin, FSH, LH, or TSH — even at doses more than 200-fold above the ED50 for GH. Earlier-generation GH-releasing peptides like GHRP-2 and GHRP-6 raise cortisol and prolactin in parallel with GH; Ipamorelin's clean GH-only signal is what made it the practitioner-default selective secretagogue and the molecular template for later compounds in the class.

The selectivity finding rests on animal pharmacology and cell-culture work, not human clinical trials. Subsequent human pharmacokinetic and small-cohort studies have been published, but Ipamorelin was never developed to large-scale clinical approval — Novo Nordisk discontinued the program before Phase III. Most of what is now described as "the human clinical experience with Ipamorelin" is therefore practitioner observation, small academic studies, and mechanistic extrapolation from the rodent and swine data this paper helped anchor. The paper is also old enough that the receptor was identified at the time as the "GHRP receptor"; later work renamed it the growth-hormone-secretagogue receptor (GHSR-1a) and identified ghrelin as its endogenous ligand. The mechanistic claim has held up; the clinical-translation work remains incomplete.