RESUMEN
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.
Asunto(s)
Bencimidazoles/química , Piperidinas/química , Receptores de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/química , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Cobayas , Semivida , Mucosa Intestinal/metabolismo , Masculino , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/farmacocinética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Agonistas del Receptor de Serotonina 5-HT4/farmacocinéticaRESUMEN
BACKGROUND: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. RESULTS: AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. CONCLUSIONS: AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.