RESUMEN
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Asunto(s)
Compuestos de Anilina/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Sulfonamidas/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.