RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.
Asunto(s)
Amidas/química , Oxadiazoles/química , Oxadiazoles/farmacología , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Animales , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Ratas , Ratas Wistar , Agonistas del Receptor de Serotonina 5-HT4/farmacocinética , Relación Estructura-ActividadRESUMEN
In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Piperidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Inhibidores de la Colinesterasa/química , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Cobayas , Humanos , Ligandos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Endogámicos , Terapia Molecular Dirigida , Piperidinas/administración & dosificación , Piperidinas/química , Receptores de Serotonina 5-HT4/metabolismo , Relación Estructura-Actividad , Pruebas de Toxicidad AgudaRESUMEN
The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.