Discovery of Nirmatrelvir (PF-07321332): A Potent, Orally Active Inhibitor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) Main Protease

In
early 2020, severe acute respiratory syndrome coronavirus
2
(SARS CoV-2) infections leading to COVID-19 disease reached a global
level leading to the World Health Organization (WHO) declaration of
a pandemic. Scientists around the globe rapidly responded to try and
discover novel therapeutics and repurpose extant drugs to treat the
disease. This work describes the preclinical discovery efforts that
led to the invention of PF-07321332 (nirmatrelvir, 14), a potent and orally active inhibitor of the SARS CoV-2 main protease
(Mpro) enzyme. At the outset we focused on modifying PF-00835231
(1) discovered in 2004 as a potent inhibitor of the SARS
CoV-1 Mpro with poor systemic exposure. Our effort was
focused on modifying 1 with the goal of engineering in
oral bioavailability by design, while maintaining cellular potency
and low metabolic clearance. Modifications of 1 ultimately
led to the invention of nirmatrelvir 14, the Mpro inhibitor component in PAXLOVID.