RESUMEN
RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Humanos , Pruebas de Sensibilidad Microbiana , Unión Proteica , Proteínas Virales de Fusión/metabolismoRESUMEN
A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Quinoxalinas/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Quinoxalinas/química , Relación Estructura-ActividadRESUMEN
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.