RESUMEN
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Asunto(s)
Analgésicos/síntesis química , Piridinas/síntesis química , Piridinas/uso terapéutico , Receptor Cannabinoide CB2/agonistas , Amidas/síntesis química , Amidas/farmacología , Amidas/uso terapéutico , Analgesia/métodos , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Inflamación , Dolor/tratamiento farmacológico , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Piridinas/síntesis química , Animales , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Piridinas/farmacología , Relación Estructura-Actividad , AguaRESUMEN
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2).
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Piridinas/síntesis química , Animales , Quinasas CDC2-CDC28/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
