Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha2-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 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.
Schwarz
Jacob B
JB
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. jacob.schwartz@pfizer.com
Gibbons
Sian E
SE
Graham
Shelley R
SR
Colbry
Norman L
NL
Guzzo
Peter R
PR
Le
Van-Duc
VD
Vartanian
Mark G
MG
Kinsora
Jack J
JJ
Lotarski
Susan M
SM
Li
Zheng
Z
Dickerson
Melvin R
MR
Su
Ti-Zhi
TZ
Weber
Mark L
ML
El-Kattan
Ayman
A
Thorpe
Andrew J
AJ
Donevan
Sean D
SD
Taylor
Charles P
CP
Wustrow
David J
DJ
D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D027062:Amino Acid Transport System L / Q000378:metabolism; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003500:Cyclization; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077206:Gabapentin; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009570:Nitriles / Q000737:chemistry; D000069583:Pregabalin; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000588:Amines; D027062:Amino Acid Transport System L; D000596:Amino Acids; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D009570:Nitriles; D021122:Protein Subunits; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin