RESUMEN
The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Éteres/síntesis química , Sulfonamidas/síntesis química , Animales , Línea Celular , Técnicas Químicas Combinatorias , Humanos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Hiperalgesia/tratamiento farmacológico , Naftalenos/síntesis química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
New, improved conditions have been developed and optimized for the synthesis of benzimidazoles by intramolecular palladium-catalyzed aryl-amination chemistry. This methodology, combined with a "catch and release" purification strategy, has led to a range of these heterocycles being prepared rapidly and in excellent yield.