RESUMEN
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Asunto(s)
Aminas , Ácidos Ciclohexanocarboxílicos , Osteoartritis/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Encéfalo/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Gabapentina , Factores de Transcripción de Octámeros , Transportadores de Anión Orgánico , Oxadiazoles/farmacología , Pregabalina , RatasRESUMEN
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacología , Tetrazoles/química , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/farmacología , Aminas/química , Animales , Anticonvulsivantes/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Gabapentina , Técnicas In Vitro , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/químicaRESUMEN
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
