Article
Author: Martinez Alsina, Luis A. ; Aschenbrenner, Lisa M. ; Behzadi, Mohammad Amin ; Greasley, Samantha E. ; Yurgelonis, Irina ; Buzon, Leanne M. ; Yang, Qingyi ; Ferre, Rose Ann ; Sharma, Raman ; Greenfield, Siennah R. ; Arcari, Joel T. ; Sakata, Sylvie ; Farley, Kathleen A. ; Di, Li ; Patel, Nandini C. ; Rai, Devendra K. ; Lian, Yajing ; Reese, Matthew R. ; Noell, Stephen ; Obach, R. Scott ; Rothan, Hussin A. ; Steppan, Claire M. ; Bechle, Bruce M. ; Sammons, Matthew F. ; Dantonio, Alyssa ; Carlo, Anthony A. ; Kalgutkar, Amit S. ; Boras, Britton ; Avery, Melissa ; Lovett, Gabrielle H. ; Gibson, Scott A. ; Hurst, Brett L. ; Lanyon, Lorraine F. ; Allerton, Charlotte M. N. ; Cardin, Rhonda D. ; Liu, Wei ; Gernhardt, Steven S. ; Sathish, Jean G. ; Verhoest, Patrick R. ; Tuttle, Jamison B. ; Wei, Liuqing ; Coffman, Karen J. ; Owen, Dafydd R. ; Catlin, Natasha R. ; Zhu, Yuao ; Eng, Heather ; Kimito, Emi
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 vs. 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 preclin. in vivo pharmacokinetics and metabolism studies in human matrixes 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.