Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin.
A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.
Hansen
T K
TK
Novo Nordisk, Novo Nordisk Park, 2760, Måløv, Denmark. tkha@novonordisk.com
Ankersen
M
M
Raun
K
K
Hansen
B S
BS
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013006:Growth Hormone / Q000187:drug effects* / Q000378:metabolism; D006728:Hormones / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
D004151:Dipeptides; D006728:Hormones; D007211:Indoles; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; D013006:Growth Hormone; C120631:tabimorelin; C094817:ibutamoren mesylate; C114611:ipamorelin