RESUMEN
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.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Epilepsia Refleja/prevención & control , Ácido gamma-Aminobutírico/análogos & derivados , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Anticonvulsivantes/química , Sitios de Unión , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Gabapentina , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Pregabalina , Subunidades de Proteína/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
