The influence of conformational restriction in the C-terminus of growth hormone secretagogues on their potency.
In order to obtain more potent growth hormone secretagogues, a comparison of ipamorelin and NN703 suggested the addition of a polar group at the C-terminus of NN703. A study was conducted using constrained amines for this purpose. Here, substituted 4-piperidinylamino- and 4-dimethylaminopiperidino-substituents were found to give the most active compounds. A replacement of the 4-dimethylaminopiperidino-substituent with 4-hydroxypiperidino resulted in a series of compounds, which showed in vitro activity with EC(50) values in the low nanomolar range, and favourable kinetic properties, such as 40% oral bioavailability. The most promising compound was also tested in a swine in vivo model, resulting in a growth hormone level with a C(max) of over 40 ng mL(-1).
Peschke
Bernd
B
Discovery Chemistry, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. bpes@novonordisk.com
Ankersen
Michael
M
Bauer
Michael
M
Hansen
Thomas Kruse
TK
Hansen
Birgit Sehested
BS
Nielsen
Karin Kramer
KK
Raun
Kirsten
K
Richter
Lutz
L
Westergaard
Lisbet
L
D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006728:Hormones / Q000737:chemistry* / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000378:metabolism*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008745:Methylation; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013552:Swine
D004151:Dipeptides; D006728:Hormones; D007202:Indicators and Reagents; D009842:Oligopeptides; D019382:Human Growth Hormone; C120631:tabimorelin; C114611:ipamorelin