RESUMEN
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Asunto(s)
Analgésicos/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Adyuvante de Freund/farmacología , Humanos , Hiperalgesia/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/uso terapéutico , Ratas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
The combination of SmI2 and the conjugate base of triethylurea (TEU-) has been shown to favor the cyclization of unsaturated halides over direct reduction to a much greater extent than other SmI2-based reductants. Aryl, heteroaryl, and alkyl halides (X = Br, Cl, F) readily undergo heterocyclization and carbocyclization in the presence of SmI2/TEU-.