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, <b>14</b>), a potent and orally active inhibitor of the SARS CoV-2 main protease (M<sup>pro</sup>) enzyme. At the outset we focused on modifying PF-00835231 (<b>1</b>) discovered in 2004 as a potent inhibitor of the SARS CoV-1 M<sup>pro</sup> with poor systemic exposure. Our effort was focused on modifying <b>1</b> with the goal of engineering in oral bioavailability by design, while maintaining cellular potency and low metabolic clearance. Modifications of <b>1</b> ultimately led to the invention of nirmatrelvir <b>14</b>, the M<sup>pro</sup> inhibitor component in PAXLOVID.
Authors
- Alyssa Dantonio (ORCID: https://orcid.org/0000-0001-9067-3660)
- Yuao Zhu (ORCID: https://orcid.org/0000-0001-9831-6836)
- Eugene P. Kadar (ORCID: https://orcid.org/0000-0003-3724-6517)
- Kathleen A. Farley (ORCID: https://orcid.org/0000-0001-8935-6852)
- Qingyi Yang (ORCID: https://orcid.org/0000-0001-5269-0494)
- Annaliesa S. Anderson (ORCID: https://orcid.org/0000-0002-6413-1718)
- Charlotte Allerton (ORCID: https://orcid.org/0000-0001-8665-159X)
- K.S. Gajiwala (ORCID: https://orcid.org/0000-0003-0338-2529)
- Anthony Carlo
- Nandini C. Patel (ORCID: https://orcid.org/0000-0002-2735-7662)
- K. Devendra (ORCID: https://orcid.org/0000-0002-1414-4676)
- Claire M. Steppan (ORCID: https://orcid.org/0000-0002-2609-7707)
- Brett L. Hurst (ORCID: https://orcid.org/0000-0003-1025-5878)
- Karen J. Coffman (ORCID: https://orcid.org/0000-0001-6164-7500)
- Erik LaChapelle
- Rhonda D. Cardin (ORCID: https://orcid.org/0000-0003-2390-8591)
- Jamison B. Tuttle (ORCID: https://orcid.org/0009-0002-7201-7074)
- Luis Martinez-Alsina (ORCID: https://orcid.org/0009-0000-1847-9556)
- Joel T. Arcari
- Heather Eng (ORCID: https://orcid.org/0000-0002-2914-3967)
- R. Scott Obach (ORCID: https://orcid.org/0000-0002-6604-401X)
- Christophe Allais (ORCID: https://orcid.org/0000-0002-3443-9391)
- M. F. Sammons (ORCID: https://orcid.org/0000-0001-6472-0646)
- Justin Bellenger (ORCID: https://orcid.org/0000-0001-5029-8114)
- Lawrence W. Updyke
- Leanne M. Buzon
- Wei Liu (ORCID: https://orcid.org/0009-0004-6667-2341)
- Brian P. Boscoe
- Kevin Ogilvie (ORCID: https://orcid.org/0000-0002-1024-2172)
- S.E. Greasley (ORCID: https://orcid.org/0000-0002-7978-6477)
- Britton Boras (ORCID: https://orcid.org/0000-0003-3624-9177)
- Dafydd R. Owen (ORCID: https://orcid.org/0000-0003-3106-7809)
- Stephen W. Wright (ORCID: https://orcid.org/0000-0002-9785-5077)
- Lorraine F. Lanyon
- Ravi Shankar Prasad Singh (ORCID: https://orcid.org/0000-0001-6298-8219)
- Sylvie K. Sakata (ORCID: https://orcid.org/0009-0003-2314-3979)
- Liuqing Wei (ORCID: https://orcid.org/0000-0003-1992-7714)
- Jean G. Sathish (ORCID: https://orcid.org/0000-0002-5605-6957)
- Rose Ann Ferre (ORCID: https://orcid.org/0000-0001-7462-1879)
- Martin Pettersson (ORCID: https://orcid.org/0000-0001-8748-9539)
- Stephen Noell (ORCID: https://orcid.org/0000-0003-3054-2575)
- Raman Sharma (ORCID: https://orcid.org/0000-0002-5437-5743)
- Lisa Aschenbrenner (ORCID: https://orcid.org/0009-0005-2921-068X)
- Jonathan J. Novak (ORCID: https://orcid.org/0000-0002-3635-7955)
- Jack C. Lee (ORCID: https://orcid.org/0000-0003-0477-8568)
- Yajing Lian
- Matthew R. Reese (ORCID: https://orcid.org/0000-0002-1066-2652)
- Eddie Yang
- Simon Berritt (ORCID: https://orcid.org/0000-0001-5572-6771)
- Stephen W. Mason (ORCID: https://orcid.org/0000-0002-6662-9624)
- Steven V. O’Neil (ORCID: https://orcid.org/0000-0002-0458-2322)
- Amit S.S. Kalgutkar (ORCID: https://orcid.org/0000-0001-9701-756X)
- Patrick R. Verhoest
- Li Di (ORCID: https://orcid.org/0000-0001-6117-9022)
- Jisun Lee (ORCID: https://orcid.org/0000-0003-1750-0063)
- Gregory Ostner
- Al Stewart
- Melissa Avery
- Scott Gibson
Institutions
- Utah State University (US)
- Pfizer (United States) (US)
- PRX Research
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02561
- Citations
- 16
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 24.07