RESUMEN
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.
Asunto(s)
Piperidinas/farmacología , Piperidinas/uso terapéutico , Antagonistas del Receptor de Serotonina 5-HT2 , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Perros , Evaluación Preclínica de Medicamentos , Ligandos , Estructura Molecular , Piperidinas/síntesis química , Ratas , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.
Asunto(s)
Amidinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Amidinas/metabolismo , Benzamidinas/síntesis química , Benzamidinas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Naftalenos/síntesis química , Naftalenos/metabolismo , Unión Proteica , Ensayo de Unión Radioligante , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.