Discovery of Nirmatrelvir (PF-07321332): A Potent, Orally Active Inhibitor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) Main Protease
Jamison B. Tuttle, Christophe Allais, Charlotte Allerton, Annaliesa S. Anderson, Joel T. Arcari, Lisa Aschenbrenner, Melissa Avery, Justin Bellenger, Simon Berritt, Britton Boras, Brian P. Boscoe, Leanne M. Buzon, Rhonda D. Cardin, Anthony Carlo, Karen J. Coffman, Alyssa Dantonio, Li Di, Heather Eng, Kathleen A. Farley, Rose Ann Ferre, K.S. Gajiwala, Scott Gibson, S.E. Greasley, Brett L. Hurst, Eugene P. Kadar, Amit S. Kalgutkar, Erik LaChapelle, Lorraine F. Lanyon, Jisun Lee, Jack C. Lee, Yajing Lian, Wei Liu, Luis Martinez-Alsina, Stephen W. Mason, Stephen Noell, Jonathan J. Novak, R. Scott Obach, Kevin Ogilvie, Steven V. O’Neil, Gregory Ostner, Dafydd R. Owen, Nandini C. Patel, Martin Pettersson, Ravi Shankar Prasad Singh, Devendra K. Rai, Matthew R. Reese, Sylvie K. Sakata, M. F. Sammons, Jean G. Sathish, Raman Sharma, Claire M. Steppan, Al Stewart, Lawrence W. Updyke, Patrick R. Verhoest, Liuqing Wei, Stephen W. Wright, Eddie Yang, Qingyi Yang, Yuao Zhu
Abstract
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 (M pro ) enzyme. At the outset we focused on modifying PF-00835231 ( 1 ) discovered in 2004 as a potent inhibitor of the SARS CoV-1 M pro 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 M pro inhibitor component in PAXLOVID.