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Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha2-delta protein.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2005 Apr 21; Vol. 48 (8), pp. 3026-35. - Publication Year :
- 2005
-
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.
- Subjects :
- Administration, Oral
Amines chemistry
Amines pharmacology
Amino Acid Transport System L metabolism
Animals
Anticonvulsants chemical synthesis
Anticonvulsants chemistry
Anticonvulsants pharmacology
Biological Transport, Active
Blood-Brain Barrier metabolism
CHO Cells
Calcium Channels metabolism
Cricetinae
Cricetulus
Cyclization
Cyclohexanecarboxylic Acids chemistry
Cyclohexanecarboxylic Acids pharmacology
Cyclopropanes chemistry
Cyclopropanes pharmacology
Gabapentin
In Vitro Techniques
Injections, Intraventricular
Ion Channel Gating
Male
Mice
Mice, Inbred DBA
Nitriles chemistry
Pregabalin
Protein Subunits metabolism
Rats
Rats, Sprague-Dawley
Swine
gamma-Aminobutyric Acid chemistry
gamma-Aminobutyric Acid pharmacology
Amines chemical synthesis
Amino Acids chemistry
Calcium Channels drug effects
Cyclohexanecarboxylic Acids chemical synthesis
Cyclopropanes chemical synthesis
gamma-Aminobutyric Acid analogs & derivatives
gamma-Aminobutyric Acid chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 48
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15828841
- Full Text :
- https://doi.org/10.1021/jm0491086