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
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.