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

• Published in: Journal of medicinal chemistry Vol. 68; no. 7; pp. 7003 - 7030
• Main Authors: Tuttle, Jamison B., Allais, Christophe, Allerton, Charlotte M. N., Anderson, Annaliesa S., Arcari, Joel T., Aschenbrenner, Lisa M., Avery, Melissa, Bellenger, Justin, Berritt, Simon, Boras, Britton, Boscoe, Brian P., Buzon, Leanne M., Cardin, Rhonda D., Carlo, Anthony A., Coffman, Karen J., Dantonio, Alyssa, Di, Li, Eng, Heather, Farley, Kathleen A., Ferre, Rose Ann, Gajiwala, Ketan S., Gibson, Scott A., Greasley, Samantha E., Hurst, Brett L., Kadar, Eugene P., Kalgutkar, Amit S., Lachapelle, Erik A., Lanyon, Lorraine F., Lee, Jisun, Lee, Jack, Lian, Yajing, Liu, Wei, Martínez-Alsina, Luis A., Mason, Stephen W., Noell, Stephen, Novak, Jonathan, Obach, R. Scott, Ogilvie, Kevin, O’Neil, Steven V., Ostner, Gregory, Owen, Dafydd R., Patel, Nandini C., Pettersson, Martin, Singh, Ravi Shankar, Rai, Devendra K., Reese, Matthew R., Sakata, Sylvie, Sammons, Matthew F., Sathish, Jean G., Sharma, Raman, Steppan, Claire M., Stewart, Al, Updyke, Lawrence, Verhoest, Patrick R., Wei, Liuqing, Wright, Stephen W., Yang, Eddie, Yang, Qingyi, Zhu, Yuao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.04.2025
• Subjects: Administration, Oral; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - metabolism; COVID-19 Drug Treatment; Drug Discovery; Humans; Lactams; Leucine; Nitriles; Proline; Protease Inhibitors - administration & dosage; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Rats; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02561

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.