Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration
Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration
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DOI：
10.1021/jm9909645
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发表时间：
2000-05-04
影响因子：
7.3
通讯作者：
Agerso, H
中科院分区：
文献类型：
--
作者：
Knudsen, LB;Nielsen, PF;Agerso, H
描述了30个氨基酸的肽激素胰高血糖素样肽-1（GLP-1）的一系列非常有效的衍生物。这些化合物都是用脂肪酸衍生的，以通过促进与血清白蛋白的结合来延长其作用。GLP-1对克隆的人GLP-1受体具有效价（EC 50为55 pM）。许多化合物具有相似或甚至更高的效力，尽管取代基相当大。与GLP-1相比，用等于或长于12个碳原子的脂肪酸衍生的所有化合物都非常持久，因此似乎适合每日一次给予2型糖尿病患者。得到了结构-活性关系。GLP-1可以用直链脂肪酸衍生，最长可达16个碳原子，有时更长，几乎在C-末端部分的任何位置，而不会显著损失效力。用两个脂肪酸取代基衍生化导致相当大的效力损失。得到了特定氨基酸衍生化的构效关系。发现脂肪酸的时间越长，失去的效力越多。同时修饰N-末端以获得更好的代谢稳定性）干扰脂肪酸衍生化并导致效力损失。
A series of very potent derivatives of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compounds were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC50 of 55 pM for the cloned human GLP-1 receptor. Many of the compounds had similar or even higher potencies, despite quite large substituents. All compounds derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization of specific amino acids generally was obtained. It was found that the longer the fatty acid, the more potency was lost. Simultaneous modification of the N-terminus tin order to obtain better metabolic stability) interfered with fatty acid derivatization and led to loss of potency.