title: Large amino acid transporter 1 (LAT1) prodrugs of valproic acid: new prodrug design ideas for central nervous system delivery.
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.
authors.affiliation: School of Pharmacy, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland. lauri.peura@uef.fi
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.forename: Kalle
authors.initials: K
authors.lastname: Malmioja
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.forename: Antti
authors.initials: A
authors.lastname: Isotalo
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D001927:Brain Diseases / Q000188:drug therapy; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004355:Drug Stability; D008401:Gas Chromatography-Mass Spectrometry; D007261:Infusions, Intra-Arterial; D007536:Isomerism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D027283:Large Neutral Amino Acid-Transporter 1; D011355:Prodrugs; D010649:Phenylalanine; D014635:Valproic Acid