{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lizzadro L"],"funding":["National Institute of Allergy and Infectious Diseases","Gladstone Institutes","NIAID NIH HHS","Roddenberry Foundation","P. and E. Taft"],"pagination":["1530-1551"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12834036"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["69(2)"],"pubmed_abstract":["The main proteases (M<sup>Pro</sup>) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M<sup>Pro</sup> 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<sup>Pro</sup> 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 (<i>M</i>)-AVI-4773 (5-(5,6-difluoro-1<i>H</i>-benzo[<i>d</i>][1,2,3]triazol-1-yl)-3-((<i>M</i>)-isoquinolin-4-yl)-6-met"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models."],"pmcid":["PMC12834036"],"funding_grant_id":["U19AI171110","U19 AI171110","G20AI174733"],"pubmed_authors":["Garcia-Sastre A","McCann JT","Renslo AR","Lizzadro L","Degotte G","Albrecht R","Henderson WR","Suazo ID","Craik CS","Hantz ER","Settineri NS","White KM","Diallo A","McGovern BL","Verba KA","Krogan NJ","Li J","Zapatero-Belinchon FJ","Montano M","Detomasi TC","Benjamin J","Taha TY","Gordon ME","Shoichet BK","Diaz-Tapia R","Huang S","Ott M","Matsui Y","Rosecrans J","Torres Pomares DF"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models.","description":"The main proteases (M<sup>Pro</sup>) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M<sup>Pro</sup> 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<sup>Pro</sup> 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 (<i>M</i>)-AVI-4773 (5-(5,6-difluoro-1<i>H</i>-benzo[<i>d</i>][1,2,3]triazol-1-yl)-3-((<i>M</i>)-isoquinolin-4-yl)-6-met","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Jan","modification":"2026-06-09T07:21:21.365Z","creation":"2026-06-09T03:11:28.424Z"},"accession":"S-EPMC12834036","cross_references":{"pubmed":["41490206"],"doi":["10.1021/acs.jmedchem.5c03015"]}}