Nonpeptidyl mimetics are developed and studied. MK-0677 was derived from GHRP-6 and developed by Merk. This entire process enabled modeling of the never before seen GHR and led to the eventual discovery of the native ligand.
Originally Posted by poopypants
Nonpeptidyl mimetics have been developed & are currently being investigated that are derivatives of the GHRP Ipamorelin...
There is no need to try to come up with a delivery system because these compounds are small molecules NOT lengthy amino acid chains. They are bioavailable.
You can go read Roy G. Smith's long but detailed account on their development in Development of Growth Hormone Secretagogues, Endocrine Reviews 26 (3): 346-360
Upon investigating its mechanism of action, we determined that GHRP-6 appeared to act through a novel receptor. Its activity was not blocked by the opiate receptor antagonist naloxone; furthermore, it was not a GHRH receptor agonist or a somatostatin receptor (sst) antagonist. Subsequently, my laboratory showed that GHRP-6 had two very important properties that made it an ideal prototype for the design of small molecules that would increase the amplitude of endogenous GH pulsatility; remarkably, in pituitary cells GHRP-6 amplified the GHRH signal transduction pathway and behaved as a functional antagonist of somatostatin.
We sought a drug candidate with high oral bioavailability and pharmacokinetics suitable for once daily administration. Although GHRP-6 itself had properties consistent with an amplifier of GH release, GHRP-6 had poor oral bioavailability (0.3%) and short in vivo half-life (20 min) in humans (29). Furthermore, as a peptide it did not readily lend itself to optimization of pharmacokinetic properties by medicinal chemistry. Hence, GHRP-6 was selected only as a model structure; our objective was to design a nonpeptide mimetic. The probability of identifying a nonpeptide mimetic of GHRH was considered low because native GHRH is a 44-amino acid peptide, and the smallest known homolog to exhibit biological activity was a 29-mer.
The GHRP-6 template also seemed ideal because it had been demonstrated that nonpeptide antagonists of small peptides could be designed based on a benzodiazepine template. However, an issue to be overcome at this time (1989) was the perceived difficulty of designing nonpeptide agonist mimetics. Fortunately, despite considerable resistance from some quarters, with the help of a few enthusiastic medicinal chemists, our efforts met with early success. Indeed, the design of GHRP-6 mimetics was considered a milestone achievement, because once we showed that such nonpeptide mimetics could be made, many more examples were forthcoming. For example, nonpeptide agonists of the peptides cholecystokinin, angiotensin, somatostatin, and melanocortin were developed.