Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain.
ChemMedChem. 2012 Apr;7(4):618-28. doi: 10.1002/cmdc.201100504. Epub 2012 Feb 3.
We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs.
我们之前描述了一种新型前药方法，其中二肽或四肽部分通过酰胺键与各种含胺药物连接，该酰胺键可被二肽基肽酶 IV（DPPIV/CD26）活性特异性切割。本文报道了该前药方法在各种含羟基药物（伯、仲、叔或芳基羟基）中的应用。我们设计并研究了包含二肽部分（可被 DPPIV/CD26 切割）和缬氨酸的三部分前药，作为杂双功能连接物，通过代谢不稳定的酯键将二肽连接到药物的羟基上。根据化合物的性质，含羟基的前药对 DPPIV/CD26 和血清的水解具有不同的敏感性。含有伯羟基（如叠氮胸苷）或芳基实体上的羟基部分（如对乙酰氨基酚）的化合物的前药最有效地转化。相比之下，DPPIV/CD26 或血清将叔羟基转化为其母体药物的能力要低得多。许多前药的水溶性相对于其母体药物显著增加。
