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

Autor: Van Oers TJ; Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada., Piercey A; Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada., Belovodskiy A; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada., Reiz B; Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada., Donnelly BL; Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada., Vuong W; Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada., Lemieux MJ; Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada., Nieman JA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada., Auclair K; Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada., Vederas JC; Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Jazyk: angličtina
Zdroj: Organic letters [Org Lett] 2023 Aug 11; Vol. 25 (31), pp. 5885-5889. Date of Electronic Publication: 2023 Jul 31.
DOI: 10.1021/acs.orglett.3c02140
Abstrakt: Nirmatrelvir and GC373 inhibit the SARS-CoV-2 3CL protease and hinder viral replication in COVID-19. As nirmatrelvir in Paxlovid is oxidized by cytochrome P450 3A4, ritonavir is coadministered to block this. However, ritonavir undesirably alters the metabolism of other drugs. Hydrogens can be replaced with deuterium in nirmatrelvir and GC373 to slow oxidation. Results show that deuterium slows oxidation of nirmatrelvir adjacent to nitrogen by ∼40% and that the type of warhead can switch the site of oxidative metabolism.
Databáze: MEDLINE