RESUMEN
A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.
Asunto(s)
Antiinflamatorios/síntesis química , Isoquinolinas/síntesis química , Piridazinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Isoquinolinas/química , Isoquinolinas/farmacocinética , Dolor/tratamiento farmacológico , Piridazinas/química , Piridazinas/farmacocinética , Ratas , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
2-Amino-5-aryl-pyridines, exemplified by compound 1, had been identified as a synthetically tractable series of CB(2) agonists from a high-throughput screen of the GlaxoSmithKline compound collection. Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Receptor Cannabinoide CB2/agonistas , Diseño de Fármacos , Estructura Molecular , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated in the perception of pain. Here we describe the discovery and optimization of a small molecule agonist and initial docking studies of this ligand into the receptor in order to provide a suitable lead and tool compound for the elucidation of the physiological function of the receptor.
