Deuteration for Metabolic Stabilization of SARS-CoV‑2 Inhibitors GC373 and Nirmatrelvir

Nirmatrelvir and GC373 inhibit theSARS-CoV-2 3CL proteaseandhinder viral replication in COVID-19. As nirmatrelvir in Paxlovidis oxidized by cytochrome P450 3A4, ritonavir is coadministered toblock this. However, ritonavir undesirably alters the metabolism ofother drugs. Hydrogens can be replaced with deuterium in nirmatrelvirand GC373 to slow oxidation. Results show that deuterium slows oxidationof nirmatrelvir adjacent to nitrogen by & SIM;40% and that the typeof warhead can switch the site of oxidative metabolism.