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
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.
Asunto(s)
Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Antidepresivos/farmacología , Inhibidores de Captación de Dopamina/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Pirrolidinas/química , Serotonina/metabolismo , Cola (estructura animal)/efectos de los fármacosRESUMEN
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.