New highly potent dipeptidic growth hormone secretagogues with low molecular weight.
Based on NN703, low molecular weight growth hormone secretagouges (GHSs) with a reduced number of hydrogen binding sites were designed by removal of the C-terminal amide group. The compounds were highly potent in combination with high efficacy in a rat pituitary cell assay, being characterized with EC(50) values down to 0.8 nM. Selected compounds were tested in in vivo animal models. The oral bioavailability in dogs was 16-44%. Also, the ED(50) values of the compounds were determined both in dog and swine.
Peschke
B
B
Health Care Chemistry, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. bpes@novo.dk
Ankersen
M
M
Hansen
T K
TK
Hansen
B S
BS
Lau
J
J
Nielsen
K K
KK
Raun
K
K
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D013006:Growth Hormone / Q000187:drug effects / Q000378:metabolism*; D006859:Hydrogen; D008297:Male; D018716:Molecular Mimicry; D008970:Molecular Weight; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
C412576:5-methyl-5-(methylamino)-N-methyl-N-(1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide; D004151:Dipeptides; D013449:Sulfonamides; D013876:Thiophenes; D006859:Hydrogen; D013006:Growth Hormone; C120631:tabimorelin