Hansen T K, Ankersen M, Hansen B S, Raun K, Nielsen K K, Lau J, Peschke B, Lundt B F, Thøgersen H, Johansen N L, Madsen K, Andersen P H
Departments of Medicinal Chemistry Research, Assay and Cell Technology, Growth Hormone Pharmacology, and Pharmacokinetics, Health Care Discovery and Preclinical Development, Novo Nordisk A/S, Novo Nordisk Park, DK2760 Målov, Denmark.
J Med Chem. 1998 Sep 10;41(19):3705-14. doi: 10.1021/jm980197u.
A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.
已发现一类新型的生长激素释放化合物，其分子量在500至650之间。本研究的目的是获得具有口服生物利用度的生长激素促分泌剂。通过合理的方法，我们能够减小先导化合物伊帕莫林（4）的尺寸，同时通过引入主链电子等排体来降低氢键结合潜力，同时保持在猪体内的效力。使用大鼠垂体试验筛选所有化合物，并评估哪些化合物应进一步测试其在猪体内的效力和在犬体内的口服生物利用度（fpo）。大多数测试化合物的fpo在10 - 55%范围内。报告了静脉给药后在猪体内的效力，发现最有效化合物的半数有效剂量（ED50）为30 nmol/kg体重。
