Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha2-delta protein.
J Med Chem
; 48(8): 3026-35, 2005 Apr 21.
Article
em En
| MEDLINE
| ID: mdl-15828841
ABSTRACT
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Cálcio
/
Ácidos Cicloexanocarboxílicos
/
Ciclopropanos
/
Ácido gama-Aminobutírico
/
Aminas
/
Aminoácidos
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2005
Tipo de documento:
Article