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

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

doi:10.1021/acs.orglett.3c02140

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

Org Lett. 2023 Aug 11;25(31):5885-5889. doi: 10.1021/acs.orglett.3c02140. Epub 2023 Jul 31.

Affiliations

¹ Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
² Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada.
³ Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
⁴ Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.

PMID: 37523471
DOI: 10.1021/acs.orglett.3c02140

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Deuterium
Humans
Ritonavir* / pharmacology
SARS-CoV-2

Substances

nirmatrelvir and ritonavir drug combination
Ritonavir
phenylmethyl N-((1S)-1-((((1S)-1-formyl-2-(2-oxo-3-pyrrolidinyl)ethyl)amino)carbonyl)-3-methylbutyl)carbamate
Deuterium
Antiviral Agents

Grants and funding

CIHR/Canada