RESUMEN
This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Piridinas/síntesis química , Receptor de Serotonina 5-HT2A/química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/síntesis química , Animales , Diseño de Fármacos , Humanos , Cinética , Ligandos , Modelos Químicos , Conformación Molecular , Piridinas/farmacología , Ratas , Antagonistas de la Serotonina/farmacología , Sulfonas/químicaRESUMEN
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.