RESUMEN
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.
Asunto(s)
Aldehídos/química , Ciclopropanos/química , Nitrilos/química , Estructura Molecular , EstereoisomerismoRESUMEN
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.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Antagonistas de Aminoácidos Excitadores/farmacocinética , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5RESUMEN
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.
Asunto(s)
Ansiolíticos/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/fisiología , Tiazoles/síntesis química , Animales , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Ansiedad , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/química , Cinética , Modelos Moleculares , Piridinas/química , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
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.
