RESUMEN
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.
Asunto(s)
Piridinas/síntesis química , Quinolonas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
Asunto(s)
Nitrilos/síntesis química , Piridonas/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Regulación Alostérica , Animales , Encéfalo/metabolismo , Sinergismo Farmacológico , Canal de Potasio ERG1 , Electroencefalografía , Canales de Potasio Éter-A-Go-Go/fisiología , Células HEK293 , Humanos , Isomerismo , Ratones , Nitrilos/farmacocinética , Nitrilos/farmacología , Técnicas de Placa-Clamp , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Sueño REM/efectos de los fármacos , Relación Estructura-Actividad , VigiliaRESUMEN
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.