RESUMEN
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Proteasa de Coronavirus/administración & dosificación , Indoles/administración & dosificación , Leucina/administración & dosificación , Pirrolidinonas/administración & dosificación , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacocinética , Alanina/administración & dosificación , Alanina/efectos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animales , COVID-19/virología , Chlorocebus aethiops , Coronavirus Humano 229E/efectos de los fármacos , Coronavirus Humano 229E/enzimología , Inhibidores de Proteasa de Coronavirus/efectos adversos , Inhibidores de Proteasa de Coronavirus/farmacocinética , Modelos Animales de Enfermedad , Diseño de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Infusiones Intravenosas , Leucina/efectos adversos , Leucina/farmacocinética , Ratones , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Células VeroRESUMEN
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.
RESUMEN
This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.
