RESUMEN
A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.
Asunto(s)
Analgésicos/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo N/química , Ácidos Carboxílicos/química , Dihidropiridinas/química , Administración Oral , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/metabolismo , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Evaluación Preclínica de Medicamentos , Formaldehído/toxicidad , Dimensión del Dolor/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
An efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary to achieve good ee (>95% for all the tested experiments) and moderate yield. With this method, (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid cinnamyl ester was obtained and was characterized as a promising N-type calcium channel blocker with improved selectivity over L-type compared to its (-)- and racemic isomers.
