RESUMO
Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.
Assuntos
Aldeídos/química , Ciclopropanos/química , Nitrilas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5RESUMO
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.
Assuntos
Ansiolíticos/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/fisiologia , Tiazóis/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Cinética , Modelos Moleculares , Piridinas/química , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.