ABSTRACT
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.
Subject(s)
Analgesics/chemical synthesis , Pyridines/chemical synthesis , Pyridines/therapeutic use , Receptor, Cannabinoid, CB2/agonists , Amides/chemical synthesis , Amides/pharmacology , Amides/therapeutic use , Analgesia/methods , Animals , Disease Models, Animal , Drug Discovery/methods , Inflammation , Pain/drug therapy , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
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).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacology , Structure-Activity Relationship , WaterABSTRACT
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).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , CDC2-CDC28 Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
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.
