RESUMEN
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Glicina/líquido cefalorraquídeo , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Macaca fascicularis , Masculino , Metilación , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.
Asunto(s)
Azepinas/farmacología , Descubrimiento de Drogas , Síndrome del Colon Irritable/tratamiento farmacológico , Receptores de Serotonina 5-HT3/metabolismo , Administración Oral , Animales , Azepinas/administración & dosificación , Azepinas/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.