A NEW SERIES OF HIGHLY POTENT GROWTH HORMONE-RELEASING PEPTIDES DERIVED FROM IPAMORELIN

A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size an d the number of potential hydrogen-bonding sites of the compounds, a s trategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in a nesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl -D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, compar able in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailabili ty in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminom ethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioa vailability in rats.