RESUMEN
Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina , Pirazoles , Relación Estructura-Actividad , Humanos , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Animales , Estructura Molecular , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/síntesis química , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacocinética , Receptores de Orexina/metabolismo , Ratas , Relación Dosis-Respuesta a Droga , MasculinoRESUMEN
Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10µM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.
