RESUMEN
Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Dopamina/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Pirrolidinas/farmacología , Serotonina/metabolismo , Animales , Antidepresivos Tricíclicos/síntesis química , Antidepresivos Tricíclicos/química , Antidepresivos Tricíclicos/farmacocinética , Células CACO-2 , Depresión/tratamiento farmacológico , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacocinética , Inhibidores de Captación de Dopamina/farmacología , Diseño de Fármacos , Humanos , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Dolor/tratamiento farmacológico , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.
Asunto(s)
Descubrimiento de Drogas/métodos , Antagonistas del Receptor Purinérgico P2 , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacología , Animales , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica/fisiología , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3 , Relación Estructura-ActividadRESUMEN
A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.