Large amino acid transporter 1 (LAT1) prodrugs of valproic acid: new prodrug design ideas for central nervous system delivery.
Mol Pharm
; 8(5): 1857-66, 2011 Oct 03.
Article
em En
| MEDLINE
| ID: mdl-21770378
ABSTRACT
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 transporter-mediated prodrug approach.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Pró-Fármacos
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Barreira Hematoencefálica
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Desenho de Fármacos
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Fármacos do Sistema Nervoso Central
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Ácido Valproico
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Transportador 1 de Aminoácidos Neutros Grandes
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article