title: A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.
abstract: 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.
authors.affiliation: 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
authors.forename: M
authors.initials: M
authors.lastname: Ankersen
authors.forename: N L
authors.initials: NL
authors.lastname: Johansen
authors.forename: K
authors.initials: K
authors.lastname: Madsen
authors.forename: B S
authors.initials: BS
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Raun
authors.forename: K K
authors.initials: KK
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Thogersen
authors.forename: T K
authors.initials: TK
authors.lastname: Hansen
authors.forename: B
authors.initials: B
authors.lastname: Peschke
authors.forename: J
authors.initials: J
authors.lastname: Lau
authors.forename: B F
authors.initials: BF
authors.lastname: Lundt
authors.forename: P H
authors.initials: PH
authors.lastname: Andersen
mesh_terms: 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
chemical_list: 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