Ankersen M, Johansen N L, Madsen K, Hansen B S, Raun K, Nielsen K K, Thogersen H, Hansen T K, Peschke B, Lau J, Lundt B F, Andersen P H
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.
J Med Chem. 1998 Sep 10;41(19):3699-704. doi: 10.1021/jm9801962.
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.
描述了一系列源自伊帕莫林的新型生长激素促分泌素。为了获得口服生物利用度，通过减小化合物潜在氢键结合位点的大小和数量，采用了使用拟肽片段3-(氨基甲基)苯甲酸和连续主链N-甲基化的策略。该系列中的几种化合物在大鼠垂体细胞试验中具有高体外效力和功效，在麻醉大鼠中具有高体内效力和功效。四肽NNC 26-0235（3-(氨基甲基)苯甲酰-D-2Nal-N-Me-D-Phe-Lys-NH2）静脉给药后，在猪体内的效力与伊帕莫林、生长激素释放肽-2（GHRP-2）和生长激素释放肽-6（GHRP-6）相当，ED50为2 nmol/kg。NNC 26-0235在犬类中显示出10%的口服生物利用度，分别口服1.8和2.7 mg/kg剂量后，NNC 26-0235和伊帕莫林能够将基础生长激素水平提高10倍以上。三肽NNC 26-0323（3-(氨基甲基)苯甲酸-N-Me-D-2Nal-N-Me-D-Phe-ol）在体外效力中等但缺乏体内效力，在大鼠中显示出20%的口服生物利用度。
