Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha(2)-delta protein

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 a...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 48; no. 8; pp. 3026 - 3035
Main Authors Schwarz, JB, Gibbons, SE, Graham, Colbry, NL, Guzzo, PR, Le, VD, Vartanian, MG, Kinsora, JJ, Lotarski, SM, Li, Z, Dickerson, MR, Su, TZ, Weber, ML, El-Kattan, A, Thorpe, AJ, Donevan, SD, Taylor, CP, Wustrow, DJ
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 21.04.2005
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
TRANSPORT
SLICES
INHIBITION
HIGH-AFFINITY LIGANDS
BIOLOGICAL EVALUATION
RELEASE
SPECTRUM
ALPHADELTA SUBUNIT
IDENTIFICATION
DERIVATIVES
Online AccessGet full text

Cover

More Information
Summary: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-beta 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0491086