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 (M Pro ) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M Pro 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 M Pro 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-1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-(( M )-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1 H,3 H )-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.