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

被引：30

作者：

Allerton, Charlotte M. N. ^{[1
]}

Arcari, Joel T. ^{[2
]}

Aschenbrenner, Lisa M. ^{[2
]}

Avery, Melissa ^{[2
]}

Bechle, Bruce M. ^{[2
]}

Behzadi, Mohammad Amin ^{[3
]}

Boras, Britton ^{[4
]}

Buzon, Leanne M. ^{[2
]}

Cardin, Rhonda D. ^{[3
]}

Catlin, Natasha R. ^{[2
]}

Carlo, Anthony A. ^{[2
]}

Coffman, Karen J. ^{[2
]}

Dantonio, Alyssa ^{[2
]}

Di, Li ^{[2
]}

Eng, Heather ^{[2
]}

Farley, Kathleen A. ^{[2
]}

Ferre, Rose Ann ^{[4
]}

Gernhardt, Steven S. ^{[2
]}

Gibson, Scott A. ^{[5
]}

Greasley, Samantha E. ^{[4
]}

Greenfield, Siennah R. ^{[1
]}

Hurst, Brett L. ^{[5
]}

Kalgutkar, Amit S. ^{[1
]}

Kimoto, Emi ^{[2
]}

Lanyon, Lorraine F. ^{[2
]}

Lovett, Gabrielle H. ^{[1
]}

Lian, Yajing ^{[2
]}

Liu, Wei ^{[4
]}

Alsina, Luis A. Martinez ^{[2
]}

Noell, Stephen ^{[2
]}

Obach, R. Scott ^{[2
]}

Owen, Dafydd R. ^{[1
]}

Patel, Nandini C. ^{[1
]}

Rai, Devendra K. ^{[2
]}

Reese, Matthew R. ^{[2
]}

Rothan, Hussin A. ^{[3
]}

Sakata, Sylvie ^{[4
]}

Sammons, Matthew F. ^{[1
]}

Sathish, Jean G. ^{[3
]}

Sharma, Raman ^{[2
]}

Steppan, Claire M. ^{[2
]}

Tuttle, Jamison B. ^{[1
]}

Verhoest, Patrick R. ^{[1
]}

Wei, Liuqing ^{[2
]}

Yang, Qingyi ^{[1
]}

Yurgelonis, Irina ^{[3
]}

Zhu, Yuao ^{[3
]}

机构：

[1] Pfizer Res & Dev, Cambridge, MA 02139 USA

[2] Pfizer Res & Dev, Groton, CT 06340 USA

[3] Pfizer Res & Dev, Pearl River, NY 10965 USA

[4] Pfizer Res & Dev, La Jolla, CA 92121 USA

[5] Utah State Univ, Inst Antiviral Res, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 16期

关键词：

ALCOHOLS; ASSAYS;

D O I：

10.1021/acs.jmedchem.3c02469

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：13550 / 13571

页数：22

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