RESUMEN
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Asunto(s)
Isoquinolinas/farmacología , Dolor/tratamiento farmacológico , Profármacos/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Administración Oral , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Haplorrinos , Isoquinolinas/química , Datos de Secuencia Molecular , Profármacos/química , Receptores de Ácido Kaínico/química , Relación Estructura-ActividadRESUMEN
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
