RESUMEN
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Asunto(s)
Antipsicóticos/química , Compuestos Heterocíclicos con 2 Anillos/química , Imidazoles/química , Pirimidinonas/química , Receptor del Glutamato Metabotropico 5/química , Regulación Alostérica , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Locomoción/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Ratas , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-ActividadRESUMEN
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.