Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models

J Med Chem. 2026 Jan 22;69(2):1530-1551. doi: 10.1021/acs.jmedchem.5c03015. Epub 2026 Jan 5.

Abstract

The main proteases (MPro) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core MPro inhibitors derived from AVI-4516, an in vivo active lead bearing an unactivated propargyl warhead. To expand the anticoronaviral spectrum, we introduced diverse C6 substitution to target the S1' pocket in MPro and observed enhanced cellular activity against various nirmatrelvir-resistant mutants. Pharmacokinetic profiling of 12 analogs revealed overall inferior exposure of the C6 aryl analogs. However, PK profiling across three species identified the improved atropisomeric lead (M)-AVI-4773 (5-(5,6-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-3-((M)-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione), which exhibits rapid-onset oral efficacy in both SARS-CoV-2 and Middle East respiratory syndrome (MERS) mouse models, highlighting a promising chemotype with the potential to deliver anticoronaviral development candidates.

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacokinetics
  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • Brain* / drug effects
  • Brain* / metabolism
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / metabolism
  • Disease Models, Animal
  • Dogs
  • Drug Discovery
  • Humans
  • Male
  • Mice
  • Middle East Respiratory Syndrome Coronavirus* / drug effects
  • Middle East Respiratory Syndrome Coronavirus* / enzymology
  • Protease Inhibitors* / administration & dosage
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacokinetics
  • Protease Inhibitors* / pharmacology
  • Protease Inhibitors* / therapeutic use
  • Rats
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / enzymology
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Protease Inhibitors
  • Coronavirus 3C Proteases