Document Detail

Large Amino Acid Transporter 1 (LAT1) Prodrugs of Valproic Acid: New Prodrug Design Ideas for Central Nervous System Delivery.
MedLine Citation:
PMID:  21770378     Owner:  NLM     Status:  Publisher    
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 prodrug approach. In this study, we designed four phenylalanine derivatives of valproic acid and studied their ability to utilize large amino acid transporter (LAT1) in CNS delivery with an aim to show that the meta-substituted phenylalanine prodrugs bind to LAT1 with higher affinity compared with the affinity of the para-substituted derivatives. All the prodrugs crossed the BBB carrier-mediatedly via large amino acid transporter 1 (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 important 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 transporter-mediated prodrug approach.
Lauri Tobias Peura; Kalle Malmioja; Krista Laine; Jukka Leppänen; Mikko Gynther; Antti Isotalo; Jarkko Rautio
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-19
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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