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 and the number of potential hydrogen-bonding sites of the compounds, a strategy 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 anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable 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 bioavailability 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-(aminomethyl)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 bioavailability in rats.
Ankersen
M
M
Departments of Medicinal Chemistry Research, Assay and Cell Technology, Growth Hormone Pharmacology, Health Care Discovery and Preclinical Development, Novo Nordisk Park, DK-2760 Måløv, Denmark. miak@novo.dk
Johansen
N L
NL
Madsen
K
K
Hansen
B S
BS
Raun
K
K
Nielsen
K K
KK
Thogersen
H
H
Hansen
T K
TK
Peschke
B
B
Lau
J
J
Lundt
B F
BF
Andersen
P H
PH
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D006728:Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
D006728:Hormones; C114612:NNC 26-0235; C114613:NNC 26-0323; D009842:Oligopeptides; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; C091874:growth hormone-releasing peptide-2; C114611:ipamorelin