ABSTRACT
A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/metabolism , Anxiety Disorders/drug therapy , Dogs , Half-Life , Ligands , Metabolic Clearance Rate , Pyridines/chemical synthesis , Pyridines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine core is described. Individual analogues were synthesized and tested in vitro in rat brain receptors to determine binding affinity. The best compound was further tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at 1 mg/kg po.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Administration, Oral , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/metabolism , Anxiety Disorders/drug therapy , Biological Availability , Dogs , Ligands , Pyridines/chemical synthesis , Pyridines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands. Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.