RESUMEN
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Asunto(s)
Amidinas/química , Química Farmacéutica/métodos , Canales de Sodio/química , Canales Iónicos Sensibles al Ácido , Animales , Diseño de Fármacos , Electrofisiología , Indoles/química , Concentración 50 Inhibidora , Canales Iónicos/química , Masculino , Modelos Químicos , Naproxeno/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Asunto(s)
Acetamidas/síntesis química , Amidas/síntesis química , Compuestos de Aminobifenilo/síntesis química , Benzoatos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Encéfalo/metabolismo , Ciclopropanos/síntesis química , Médula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacología , Administración Oral , Amidas/farmacocinética , Amidas/farmacología , Compuestos de Aminobifenilo/farmacocinética , Compuestos de Aminobifenilo/farmacología , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Animales , Animales Modificados Genéticamente , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Disponibilidad Biológica , Barrera Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Femenino , Humanos , Macaca mulatta , Masculino , Ratones , Conejos , Ensayo de Unión Radioligante , Ratas , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
Bradykinin B1 receptor antagonists embody a potentially novel approach for the treatment of chronic pain and inflammation. A series of 2,3-diaminopyridine B1 antagonists was optimized to have sub-nanomolar affinity and good pharmacokinetic properties. Lead compounds were shown to exhibit good efficacy in rabbit in vivo models of pain and inflammation.