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

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

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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