RESUMO
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.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Ácidos Carboxílicos/química , Epilepsia Reflexa/prevenção & controle , Ácido gama-Aminobutírico/análogos & derivados , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Anticonvulsivantes/química , Sítios de Ligação , Ácidos Cicloexanocarboxílicos/síntese química , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Gabapentina , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Pregabalina , Subunidades Proteicas/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/síntese química , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologiaRESUMO
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.
