A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19
Charlotte Allerton, Joel T. Arcari, Lisa Aschenbrenner, Melissa Avery, Bruce M. Bechle, Mohammad Amin Behzadi, Britton Boras, Leanne M. Buzon, Rhonda D. Cardin, Natasha R. Catlin, Anthony Carlo, Karen J. Coffman, Alyssa Dantonio, Li Di, Heather Eng, Kathleen A. Farley, Rose Ann Ferre, Steven Gernhardt, Scott Gibson, S.E. Greasley, Siennah R. Greenfield, Brett L. Hurst, Amit S. Kalgutkar, Emi Kimoto, Lorraine F. Lanyon, Gabrielle H. Lovett, Yajing Lian, Wei Liu, Luis Martinez-Alsina, Stephen Noell, R. Scott Obach, Dafydd R. Owen, Nandini C. Patel, Devendra K. Rai, Matthew R. Reese, Hussin A. Rothan, Sylvie K. Sakata, M. F. Sammons, Jean G. Sathish, Raman Sharma, Claire M. Steppan, Jamison B. Tuttle, Patrick R. Verhoest, Liuqing Wei, Qingyi Yang, Irina Yurgelonis, Yuao Zhu
Abstract
High Resolution Image Download MS PowerPoint Slide 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.