Growth hormone is a protein, GHRH and the somatomedins family are peptides and are therapeutically available as such. At this time, none of the more recent Growth Hormone Releasing Peptides and their non-peptidyl mimetics have been approved for treatment, but it is Ukely that one or more GH secretagogues will eventually become therapeutic agents. Cyril Y. Bowers, the discoverer of the original GHRP series has reviewed their history. Other excellent reviews of this new class of GH Secretagogues have been published. Following the trailblazer, seminal work of Bowers and Momany, ourselves, and groups from Genentech and Novo Nordisk have developed peptidyl analogues of Bowers' GHRP-6. In the non-peptidyl series, researchers from Merck Research Laboratories are unquestionably in the lead and their spiropiperidine derivative MK-0677 has been the most studied GHS drug candidate. Other groups from Pfizer and Lilly have disclosed in the patent literature their peptidomimetic GPI secretagogues.
Medicinal chemists are therefore divided between those who develop non-peptide ligands for peptide receptors and those who continue to favour peptide analogues as potential drugs. The latter have to face the additional problem of how to conveniently deliver their peptide analogues which are poorly absorbed by the oral route. One of the reasons why peptides are, with few exceptions, not absorbable orally is because of their vulnerability to proteases and peptidases present in the gastro-intestinal tract. In an attempt to minimize this problem, we developed a series of "impervious peptides", so-called because they are poor substrates to peptidases and proteases. Starting from Hexarelin, we have downsized the hexapeptide to obtain a series of smaller peptides of which the pentapeptide derivative EP 51216 and the tripeptide analogue EP 51389 have been found to be potent GH secretagogues in the infant rat and in the dog. In the latter species and indeed even in humans, the pentapeptide derivative EP 51216 elicited a GH response when given orally at doses of 0.3 to 0.6 mg/kg.
Oral bioavailability, however, is not only dependent on the "imperviousness" of peptides, or indeed even of non-peptidic molecules. Other important factors are the size of the molecule, its lipid-water partition coefficient and the related propensity of forming hydrogen bonding with the aqueous physiologic environment. An intriguing possibility is to deliver GH secretagogues by sustained release parenteral devices, such as those successfully employed in the field of LHRH analogues, if the sustained release is compatible with therapeutic efficacy and has an acceptable safety profile. Apart from an increased chemical stability, the Mrp substitution was beneficial when a D-Trp was replaced by a D-Mrp, but not when a Trp was substituted with Mrp, at least with the well known GHRP-6 structure. This observation seemed to indicate the importance of the unencumbered indole N-H of Trp for receptor binding, confirmed by the inactivity of Oxyindolalanine (Oia) derivative of Hexarelin: His-D-Mrp-Ala-Oia-D-Phe-Lys-NH2 (EP 70683, mixture of two stereoisomers) compared to HexareUn in the rat, in which the indolic N-H is perturbed by the neighbouring oxygen in position 2. If we take GHRP-6 as the model prototype, our investigations have shown that the D-Trp in position 2 can be advantageously substituted with the more stable, more hydrophobic D-2MeTrp (D-Mrp). Bowers had similarly shown that the DTrp could be substituted with a D-Nal (P-Naphthylalanine) in GHRP-2. Some or total loss of activity, as we have seen, occurs when the Trp in position 4 is replaced with the L-2MeTrp or with Oia, the oxidated form of Trp. Prolongation of the chain on the N terminal side is compatible with retention and even augmentation of activity (cf EP 930497, EP 93183). It is unlikely that the same hypothalamic, pituitary or peripheral receptors for which GHRP-6 and similar peptides are ligands, show the same specificity for shorter GHS, such as MK 0677 and EP 51389.
There is now evidence that this is indeed the case with some of the shorter GHS being unable to fully displace radioligands such as I-Tyr-Ala-His- D-Mrp-Ala-Trp-D-Phe-Lys-NH2. Experimentally the metabolic stability of GHRP-6 (SK&F 110679) or of hexarelin has been confirmed at least in the rat from which more than 50% of these peptides can be recovered unchanged in the bile following their subcutaneous administration. This observation prompted the SK&F group to observe that GHRP-6 "was not designed with metabolic stability in mind [but] it is tempting to speculate that the structural features that are important for receptor binding and pharmacological activity of these peptides may also confer metabolic stability, protecting them from degradation by peptidases". We propose the term impemouspeptides to describe the metaboUc stability characteristic of this series of secretagogues. The resistance to peptidases and protease of Hexarelin (EP23905), the pentapeptide EP51216 and the tripeptide EP 51389 was measured in vitro by incubation at 3TC for one hour in conditions that caused extensive degradation of an LHRH analogue chosen as a reference peptide. This demonstrates the resistance and high resistance of EP23905 and EP51389 respectively. Not surprisingly, EP51389 is totally resistant because of D amino acids composition.
The sensitivity of EP51216 to trypsin and protease is essentially due to the deamidation of the C-terminal amide. Surprisingly, EP 23905 (Hexarelin) is very resistant to these enzymes. Since the primary structure cannot explain this resistance, one can suggest a secondary 'cyclic' structure as having a protective effect. The peptide approach to the practical development of GH secretagogues remains a viable one, particularly when such peptides are rendered impervious and are appropriately modified to render them less polar and more absorbable by the oral route. The discovery of peripheral receptors opens new opportunities for medicinal chemists and pharmacologists for the development of organ or tissue specific agents.
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