RESUMEN
OBJECTIVE: A 5-h phase advance model of insomnia was used to evaluate the efficacy of lorediplon, a new non-benzodiazepine hypnotic. METHODS: Thirty-five male, healthy subjects were included in a five-way randomized cross-over study. During each of the periods, sleep was recorded, and residual effects were measured. All subjects received lorediplon 1, 5, and 10 mg, placebo, and zolpidem 10 mg (i.e., active control). RESULTS: Polysomnographic evaluation revealed that lorediplon (5 and 10 mg) significantly decreased wake after sleep onset (WASO) and increased total sleep time. Analysis by quarters of the night showed a progressive increasing effectiveness of lorediplon 10 mg across the first three quarters. Lorediplon increased non-rapid eye movement slow wave sleep and stage N2 sleep in the second and third quarters. The magnitude of these effects was dose related, with minimal effects seen with 1 mg. No residual effects were observed 13 h post dose. CONCLUSIONS: Lorediplon demonstrated a dose-dependent improvement in sleep, whereas zolpidem showed a more sustained WASO effect. No next-day hangover effects were observed. These sleep effects are also consistent with the pharmacokinetic profile of lorediplon. These results warrant clinical trials in patients with insomnia.
Asunto(s)
Hipnóticos y Sedantes/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Hipnóticos y Sedantes/efectos adversos , Masculino , Polisomnografía , Pirazoles/efectos adversos , Piridinas/efectos adversos , Piridinas/uso terapéutico , Pirimidinas/efectos adversos , Sueño/efectos de los fármacos , Sueño/fisiología , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Fases del Sueño/efectos de los fármacos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Población Blanca , Adulto Joven , ZolpidemRESUMEN
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.