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

• DOI: 10.1021/acs.orglett.3c02140
• Publication Date: 2023-07-31T18:13:19Z
• Authors: Tayla J. Van Oers; Alexia Piercey; Alexandr Belovodskiy; Béla Reiz; Bethan L. Donnelly; Wayne Vuong; M. Joanne Lemieux; James A. Nieman; Karine Auclair; John C. Vederas
• Keywords: Ritonavir

Nirmatrelvir and GC373 inhibit the SARS-CoV-2 3CL protease hinder viral replication in COVID-19. As nirmatrelvir Paxlovid is oxidized by cytochrome P450 3A4, ritonavir coadministered to block this. However, undesirably alters metabolism of other drugs. Hydrogens can be replaced with deuterium slow oxidation. Results show that slows oxidation adjacent nitrogen ∼40% type warhead switch site oxidative metabolism.