期刊
MOLECULAR PHARMACEUTICS
卷 8, 期 5, 页码 1857-1866出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp2001878
关键词
central nervous system; blood-brain barrier; large amino acid transporter 1; brain drug delivery; prodrugs; valproic acid
资金
- National Technology Agency of Finland (TEKES)
- Finnish Academy [132637]
- Finnish Pharmaceutical Society
- Academy of Finland (AKA) [132637, 132637] Funding Source: Academy of Finland (AKA)
Central nervous system (CNS) drug delivery is a major challenge in drug development because the blood-brain barrier (BBB) efficiently restricts the entry of drug molecules into the CNS at sufficient amounts. The brain uptake of poorly penetrating drugs could be improved by utilizing the transporters at the BBB with a prodrug approach. In this study, we designed four phenylalanine derivatives of valproic acid and studied their ability to utilize a large amino acid transporter 1 (LAT1) in CNS delivery with an aim to show that the meta-substituted phenylalanine prodrugs bind to LAT1 with a higher affinity compared with the affinity of the para-substituted derivatives. All of the prodrugs crossed the BBB carrier mediatedly via LAT1 in in situ rat brain perfusion. For the first time, we introduced a novel meta-substituted phenylalanine analogue promoiety which improved the LAT1 affinity 10-fold and more importantly the rat brain uptake of the prodrug 2-fold compared with those of the para-substituted derivatives. Therefore, we have characterized a new prodrug design idea for CNS drug delivery utilizing a transportermediated prodrug approach.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据