| Autor: |
Ankersen 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 NL, Madsen K, Hansen BS, Raun K, Nielsen KK, Thogersen H, Hansen TK, Peschke B, Lau J, Lundt BF, Andersen PH |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1998 Sep 10; Vol. 41 (19), pp. 3699-704. |
| DOI: |
10.1021/jm9801962 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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