A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19

  • J Med Chem. 2024 Apr 30. doi: 10.1021/acs.jmedchem.3c02469.
Charlotte M N Allerton  1 ,  Joel T Arcari  2 ,  Lisa M Aschenbrenner  2 ,  Melissa Avery  2 ,  Bruce M Bechle  2 ,  Mohammad Amin Behzadi  3 ,  Britton Boras  4 ,  Leanne M Buzon  2 ,  Rhonda D Cardin  3 ,  Natasha R Catlin  2 ,  Anthony A Carlo  2 ,  Karen J Coffman  2 ,  Alyssa Dantonio  2 ,  Li Di  2 ,  Heather Eng  2 ,  Kathleen A Farley  2 ,  Rose Ann Ferre  4 ,  Steven S Gernhardt  2 ,  Scott A Gibson  5 ,  Samantha E Greasley  4 ,  Siennah R Greenfield  1 ,  Brett L Hurst  5 ,  Amit S Kalgutkar  1 ,  Emi Kimoto  2 ,  Lorraine F Lanyon  2 ,  Gabrielle H Lovett  1 ,  Yajing Lian  2 ,  Wei Liu  4 ,  Luis A Martínez Alsina  2 ,  Stephen Noell  2 ,  R Scott Obach  2 ,  Dafydd R Owen  1 ,  Nandini C Patel  1 ,  Devendra K Rai  2 ,  Matthew R Reese  2 ,  Hussin A Rothan  3 ,  Sylvie Sakata  4 ,  Matthew F Sammons  1 ,  Jean G Sathish  3 ,  Raman Sharma  2 ,  Claire M Steppan  2 ,  Jamison B Tuttle  1 ,  Patrick R Verhoest  1 ,  Liuqing Wei  2 ,  Qingyi Yang  1 ,  Irina Yurgelonis  3 ,  Yuao Zhu  3
Affiliations
  • 1. Pfizer Research & Development, Cambridge, Massachusetts 02139, United States.
  • 2. Pfizer Research & Development, Groton, Connecticut 06340, United States.
  • 3. Pfizer Research & Development, Pearl River, New York 10965, United States.
  • 4. Pfizer Research & Development, La Jolla, California 92121, United States.
  • 5. Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah 84322, United States.
PMID: 38687966 DOI: 10.1021/acs.jmedchem.3c02469
Abstract

Despite the record-breaking discovery, development and approval of vaccines and Antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the Antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus Antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing Enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

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