RÉSUMÉ
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.
Sujet(s)
Analgésiques/synthèse chimique , Pyridines/synthèse chimique , Pyridines/usage thérapeutique , Récepteur cannabinoïde de type CB2/agonistes , Amides/synthèse chimique , Amides/pharmacologie , Amides/usage thérapeutique , Analgésie/méthodes , Animaux , Modèles animaux de maladie humaine , Découverte de médicament/méthodes , Inflammation , Douleur/traitement médicamenteux , Pyridines/pharmacologie , Relation structure-activitéRÉSUMÉ
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).
Sujet(s)
Glycogen Synthase Kinase 3/antagonistes et inhibiteurs , Pyridines/synthèse chimique , Animaux , Sites de fixation , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Humains , Concentration inhibitrice 50 , Pyridines/pharmacologie , Relation structure-activité , EauRÉSUMÉ
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).
Sujet(s)
Glycogen Synthase Kinase 3/antagonistes et inhibiteurs , Pyridines/synthèse chimique , Animaux , Kinases CDC2-CDC28/antagonistes et inhibiteurs , Kinase-2 cycline-dépendante , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Humains , Liaison hydrogène , Concentration inhibitrice 50 , Pyridines/pharmacologie , Relation structure-activitéRÉSUMÉ
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.