ABSTRACT
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Carboxylic Acids/chemistry , Epilepsy, Reflex/prevention & control , gamma-Aminobutyric Acid/analogs & derivatives , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Animals , Anticonvulsants/chemistry , Binding Sites , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Disease Models, Animal , Drug Evaluation, Preclinical , Gabapentin , Mice , Mice, Inbred DBA , Molecular Structure , Pregabalin , Protein Subunits/drug effects , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
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.
