RESUMEN
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.
RESUMEN
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Asunto(s)
Benzamidas/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , RoedoresRESUMEN
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal blood pressure and flow. A new series of aminopiperidines as potent inhibitors of iNOS were identified from a HTS lead. From this study, we identified compound 33 as a potent iNOS inhibitor, with >25-fold selectivity over eNOS and 16-fold selectivity over nNOS.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Aminas/química , Sitios de Unión , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Piperidinas/química , Relación Estructura-ActividadRESUMEN
[reaction: see text] Metalation of a Boc-protected N-silylamine alpha to nitrogen results in migration of the silicon from nitrogen to carbon (reverse aza-Brook rearrangement), yielding an alpha-amino silane. The Boc group acts initially as a metalation-directing group and then to stabilize the nitrogen anion, providing a driving force for the rearrangement. In the presence of (-)-sparteine, the new chiral center is formed in >90% ee from allyl, benzyl, and propargylamines.
