RESUMO
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Assuntos
Compostos Azabicíclicos/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Benzamidas/farmacologia , Proteínas Sanguíneas/efeitos dos fármacos , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Conformação Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Piridinas/síntese química , Piridinas/química , Quinuclidinas/farmacologia , Ratos , Receptores Muscarínicos/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
Assuntos
Encéfalo/metabolismo , Desenho de Fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Animais , Bungarotoxinas , Células Cultivadas , Eletrofisiologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
