RESUMEN
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lactamas/farmacología , Lactamas/uso terapéutico , Leucina/farmacología , Leucina/uso terapéutico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Prolina/farmacología , Prolina/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Inhibidores de Proteasa Viral/farmacología , Inhibidores de Proteasa Viral/uso terapéutico , Administración Oral , Animales , COVID-19/virología , Ensayos Clínicos Fase I como Asunto , Coronavirus/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Humanos , Lactamas/administración & dosificación , Lactamas/farmacocinética , Leucina/administración & dosificación , Leucina/farmacocinética , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Prolina/administración & dosificación , Prolina/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , SARS-CoV-2/fisiología , Inhibidores de Proteasa Viral/administración & dosificación , Inhibidores de Proteasa Viral/farmacocinética , Replicación Viral/efectos de los fármacosRESUMEN
Targeting viral polymerases has been a proven and attractive strategy for antiviral drug discovery. Herein we describe our effort in improving the antiviral activity and physical properties of a series of benzothienoazepine compounds as respiratory syncytial virus (RSV) RNA polymerase inhibitors. The antiviral activity and spectrum of this class was significantly improved by exploring the amino substitution of the pyridine ring, resulting in the discovery of the most potent RSV A polymerase inhibitors reported to date.