RESUMEN
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Diseño de Fármacos , Piperidinas/síntesis química , Piperidinas/farmacología , Piranos/síntesis química , Piranos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/química , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Frecuencia Cardíaca/efectos de los fármacos , Modelos Animales , Estructura Molecular , Piperidinas/química , Piranos/química , Ratas , Relación Estructura-ActividadRESUMEN
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
