An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19

Owen, D. R.; Allerton, C. M. N.; Anderson, A. S.; Aschenbrenner, L.; Avery, M.; Berritt, S.; Boras, B.; Cardin, R. D.; Carlo, A.; Coffman, K.; Dantonio, A.; Di, L.; Eng, H.; Ferre, R.; Gajiwala, K. S.; Gibson, S. A.; Greasley, S. E.; Hurst, B. L.; Kadar, E. P.; Kalgutkar, A. S.; Lee, J. C.; Lee, J.; Liu, W.; Mason, S. W.; Noell, S.; Novak, J. J.; Obach, R. S.; Ogilvie, K.; Patel, N. C.; Pettersson, M.; Rai, D. K.; Reese, M. R.; Sammons, M. F.; Sathish, J. G.; Singh, R. S. P.; Steppan, C. M.; Stewart, A. E.; Tuttle, J. B.; Updyke, L.; Verhoest, P. R.; Wei, L.; Yang, Q.; Zhu, Y.

The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity, and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency, in a phase I clinical trial in healthy human participants. Clinical Trial Registration ID #: NCT04756531