ABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Isoquinolines/chemical synthesis , Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Pain/drug therapy , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
Subject(s)
Aminopyridines/therapeutic use , Brain/metabolism , Morpholines/therapeutic use , Pain/drug therapy , Receptor, Cannabinoid, CB2/agonists , Aminopyridines/pharmacokinetics , Animals , Aza Compounds , CHO Cells , Cell Line , Chronic Disease , Cricetinae , Cricetulus , Drug Discovery , Humans , Indoles , Morpholines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
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
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.
Subject(s)
Analgesics/chemical synthesis , Pain/drug therapy , Pyrans/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Biological Availability , Half-Life , Humans , Inflammation/drug therapy , Inflammation/metabolism , Pain/metabolism , Pyrans/pharmacokinetics , Pyrans/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , 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.
