Jamison B. Tuttle*, Christophe Allais, Charlotte M. N. Allerton, Annaliesa S. Anderson, Joel T. Arcari, Lisa M. Aschenbrenner, Melissa Avery, Justin Bellenger, Simon Berritt, Britton Boras, Brian P. Boscoe, Leanne M. Buzon, Rhonda D. Cardin, Anthony A. Carlo, Karen J. Coffman, Alyssa Dantonio, Li Di, Heather Eng, Kathleen A. Farley, Rose Ann Ferre, Ketan S. Gajiwala, Scott A. Gibson, Samantha E. Greasley, Brett L. Hurst, Eugene P. Kadar, Amit S. Kalgutkar, Erik A. Lachapelle, Lorraine F. Lanyon, Jisun Lee, Jack Lee, Yajing Lian, Wei Liu, Luis A. Martínez-Alsina, Stephen W. Mason, Stephen Noell, Jonathan Novak, R. Scott Obach, Kevin Ogilvie, Steven V. O’Neil, Gregory Ostner, Dafydd R. Owen, Nandini C. Patel, Martin Pettersson, Ravi Shankar Singh, Devendra K. Rai, Matthew R. Reese, Sylvie Sakata, Matthew F. Sammons, Jean G. Sathish, Raman Sharma, Claire M. Steppan, Al Stewart, Lawrence Updyke, Patrick R. Verhoest, Liuqing Wei, Stephen W. Wright, Eddie Yang, Qingyi Yang and Yuao Zhu,
{"title":"Nirmatrelvir (PF-07321332)：一种有效的口服活性严重急性呼吸综合征冠状病毒2 （SARS CoV-2）主蛋白酶抑制剂的发现","authors":"Jamison B. Tuttle*, Christophe Allais, Charlotte M. N. Allerton, Annaliesa S. Anderson, Joel T. Arcari, Lisa M. Aschenbrenner, Melissa Avery, Justin Bellenger, Simon Berritt, Britton Boras, Brian P. Boscoe, Leanne M. Buzon, Rhonda D. Cardin, Anthony A. Carlo, Karen J. Coffman, Alyssa Dantonio, Li Di, Heather Eng, Kathleen A. Farley, Rose Ann Ferre, Ketan S. Gajiwala, Scott A. Gibson, Samantha E. Greasley, Brett L. Hurst, Eugene P. Kadar, Amit S. Kalgutkar, Erik A. Lachapelle, Lorraine F. Lanyon, Jisun Lee, Jack Lee, Yajing Lian, Wei Liu, Luis A. Martínez-Alsina, Stephen W. Mason, Stephen Noell, Jonathan Novak, R. Scott Obach, Kevin Ogilvie, Steven V. O’Neil, Gregory Ostner, Dafydd R. Owen, Nandini C. Patel, Martin Pettersson, Ravi Shankar Singh, Devendra K. Rai, Matthew R. Reese, Sylvie Sakata, Matthew F. Sammons, Jean G. Sathish, Raman Sharma, Claire M. Steppan, Al Stewart, Lawrence Updyke, Patrick R. Verhoest, Liuqing Wei, Stephen W. Wright, Eddie Yang, Qingyi Yang and Yuao Zhu, ","doi":"10.1021/acs.jmedchem.4c0256110.1021/acs.jmedchem.4c02561","DOIUrl":null,"url":null,"abstract":"<p >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.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 7","pages":"7003–7030 7003–7030"},"PeriodicalIF":6.8000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Nirmatrelvir (PF-07321332): A Potent, Orally Active Inhibitor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) Main Protease\",\"authors\":\"Jamison B. Tuttle*, Christophe Allais, Charlotte M. N. Allerton, Annaliesa S. Anderson, Joel T. Arcari, Lisa M. Aschenbrenner, Melissa Avery, Justin Bellenger, Simon Berritt, Britton Boras, Brian P. Boscoe, Leanne M. Buzon, Rhonda D. Cardin, Anthony A. Carlo, Karen J. Coffman, Alyssa Dantonio, Li Di, Heather Eng, Kathleen A. Farley, Rose Ann Ferre, Ketan S. Gajiwala, Scott A. Gibson, Samantha E. Greasley, Brett L. Hurst, Eugene P. Kadar, Amit S. Kalgutkar, Erik A. Lachapelle, Lorraine F. Lanyon, Jisun Lee, Jack Lee, Yajing Lian, Wei Liu, Luis A. Martínez-Alsina, Stephen W. Mason, Stephen Noell, Jonathan Novak, R. Scott Obach, Kevin Ogilvie, Steven V. O’Neil, Gregory Ostner, Dafydd R. Owen, Nandini C. Patel, Martin Pettersson, Ravi Shankar Singh, Devendra K. Rai, Matthew R. Reese, Sylvie Sakata, Matthew F. Sammons, Jean G. Sathish, Raman Sharma, Claire M. Steppan, Al Stewart, Lawrence Updyke, Patrick R. Verhoest, Liuqing Wei, Stephen W. 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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.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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