2. Academic Validation
  3. Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV-2 to Low-Nanomolar Antiviral Potency

Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV-2 to Low-Nanomolar Antiviral Potency

  • ACS Med Chem Lett. 2021 Jul 14;12(8):1325-1332. doi: 10.1021/acsmedchemlett.1c00326.
Chun-Hui Zhang 1,  Krasimir A Spasov 2,  Raquel A Reilly 2,  Klarissa Hollander 2 3,  Elizabeth A Stone 1,  Joseph A Ippolito 1,  Maria-Elena Liosi 1,  Maya G Deshmukh 2 4,  Julian Tirado-Rives 1,  Shuo Zhang 5,  Zhuobin Liang 6,  Scott J Miller 1,  Farren Isaacs 6,  Brett D Lindenbach 5,  Karen S Anderson 2 3,  William L Jorgensen 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
  • 2 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
  • 4 M.D.-Ph.D. Program, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
  • 5 Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536-0812, United States.
  • 6 Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
PMID: 34408808 DOI: 10.1021/acsmedchemlett.1c00326
Abstract

Non-covalent inhibitors of the main Protease (Mpro) of SARS-CoV-2 having a pyridinone core were previously reported with IC50 values as low as 0.018 μM for inhibition of enzymatic activity and EC50 values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of Mpro and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC50 values as low as 0.080 μM, while remdesivir yields values of 0.5-2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds 19 and 21 are particularly promising as potential therapies for COVID-19, featuring IC50 values of 0.044-0.061 μM, EC50 values of CA. 0.1 μM, good aqueous solubility, and no cytotoxicity.

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