RESUMEN
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
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography.
Asunto(s)
Indoles/farmacocinética , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina , Administración Oral , Animales , Células CACO-2 , Humanos , Indoles/administración & dosificación , Indoles/química , Indoles/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Antagonistas de Receptores Purinérgicos P1 , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/química , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , 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.
Asunto(s)
Síndrome del Colon Irritable/tratamiento farmacológico , Receptores de Serotonina 5-HT3/química , Agonistas del Receptor de Serotonina 5-HT3/química , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Imidazoles/química , Indoles/química , Ratones , Microsomas Hepáticos/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT3/síntesis química , Agonistas del Receptor de Serotonina 5-HT3/uso terapéuticoRESUMEN
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).