RESUMEN
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
Asunto(s)
Regulación Alostérica , Compuestos de Azabiciclo/síntesis química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Éteres/química , Receptores de Glutamato Metabotrópico/química , Administración Oral , Sitio Alostérico , Animales , Compuestos de Azabiciclo/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Microsomas/efectos de los fármacos , Modelos Químicos , Ratas , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.