An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

Science. 2021 Dec 24;374(6575):1586-1593. doi: 10.1126/science.abl4784. Epub 2021 Nov 2.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Animals
  • COVID-19 / drug therapy*
  • COVID-19 / virology
  • Clinical Trials, Phase I as Topic
  • Coronavirus / drug effects
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Humans
  • Lactams / administration & dosage
  • Lactams / pharmacokinetics
  • Lactams / pharmacology*
  • Lactams / therapeutic use*
  • Leucine / administration & dosage
  • Leucine / pharmacokinetics
  • Leucine / pharmacology*
  • Leucine / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Nitriles / administration & dosage
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use*
  • Proline / administration & dosage
  • Proline / pharmacokinetics
  • Proline / pharmacology*
  • Proline / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Ritonavir / administration & dosage
  • Ritonavir / therapeutic use
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • Viral Protease Inhibitors / administration & dosage
  • Viral Protease Inhibitors / pharmacokinetics
  • Viral Protease Inhibitors / pharmacology*
  • Viral Protease Inhibitors / therapeutic use*
  • Virus Replication / drug effects

Substances

  • Lactams
  • Nitriles
  • Viral Protease Inhibitors
  • nirmatrelvir
  • Proline
  • Leucine
  • Ritonavir

Associated data

  • figshare/10.25454/ pfizer.figshare.16699669