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

Abstract

The main proteases (M) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core Minhibitors 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 Mand 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 ()-AVI-4773 (5-(5,6-difluoro-1-benzo[][1,2,3]triazol-1-yl)-3-(()-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1,3)-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.