Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

J Med Chem. 2022 May 12;65(9):6499-6512. doi: 10.1021/acs.jmedchem.2c00117. Epub 2022 Mar 30.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19 Drug Treatment*
  • COVID-19 Vaccines
  • Coronavirus 3C Proteases
  • Humans
  • Mice
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • SARS-CoV-2*

Substances

  • Antiviral Agents
  • COVID-19 Vaccines
  • Protease Inhibitors
  • Coronavirus 3C Proteases

Supplementary concepts

  • SARS-CoV-2 variants