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^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-1H-benzo[d][1,2,3]triazol-1-yl)-3-((M)-isoquinolin-4-yl)-6-met

SUBMITTER: Lizzadro L 

PROVIDER: S-EPMC12834036 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature