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

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.