Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID-19

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, James Logue, Suman A. Luthra, Chunlong Ma, Stephen W. Mason, Marisa E. McGrath, Dafydd Owen, R. Scott Obach, Matthew N. O'Brien, Rebecca O'Connor, Kevin Ogilvie, Martin Pettersson, Matthew R. Reese, Thomas F. Rogers, Romel Rosales, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Kris M. White, Adolfo García-Sastre, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson, Charlotte Allerton