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

Autor:	Allerton CMN; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Arcari JT; Pfizer Research & Development, Groton, Connecticut 06340, United States., Aschenbrenner LM; Pfizer Research & Development, Groton, Connecticut 06340, United States., Avery M; Pfizer Research & Development, Groton, Connecticut 06340, United States., Bechle BM; Pfizer Research & Development, Groton, Connecticut 06340, United States., Behzadi MA; Pfizer Research & Development, Pearl River, New York 10965, United States., Boras B; Pfizer Research & Development, La Jolla, California 92121, United States., Buzon LM; Pfizer Research & Development, Groton, Connecticut 06340, United States., Cardin RD; Pfizer Research & Development, Pearl River, New York 10965, United States., Catlin NR; Pfizer Research & Development, Groton, Connecticut 06340, United States., Carlo AA; Pfizer Research & Development, Groton, Connecticut 06340, United States., Coffman KJ; Pfizer Research & Development, Groton, Connecticut 06340, United States., Dantonio A; Pfizer Research & Development, Groton, Connecticut 06340, United States., Di L; Pfizer Research & Development, Groton, Connecticut 06340, United States., Eng H; Pfizer Research & Development, Groton, Connecticut 06340, United States., Farley KA; Pfizer Research & Development, Groton, Connecticut 06340, United States., Ferre RA; Pfizer Research & Development, La Jolla, California 92121, United States., Gernhardt SS; Pfizer Research & Development, Groton, Connecticut 06340, United States., Gibson SA; Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah 84322, United States., Greasley SE; Pfizer Research & Development, La Jolla, California 92121, United States., Greenfield SR; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Hurst BL; Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah 84322, United States., Kalgutkar AS; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Kimoto E; Pfizer Research & Development, Groton, Connecticut 06340, United States., Lanyon LF; Pfizer Research & Development, Groton, Connecticut 06340, United States., Lovett GH; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Lian Y; Pfizer Research & Development, Groton, Connecticut 06340, United States., Liu W; Pfizer Research & Development, La Jolla, California 92121, United States., Martínez Alsina LA; Pfizer Research & Development, Groton, Connecticut 06340, United States., Noell S; Pfizer Research & Development, Groton, Connecticut 06340, United States., Obach RS; Pfizer Research & Development, Groton, Connecticut 06340, United States., Owen DR; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Patel NC; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Rai DK; Pfizer Research & Development, Groton, Connecticut 06340, United States., Reese MR; Pfizer Research & Development, Groton, Connecticut 06340, United States., Rothan HA; Pfizer Research & Development, Pearl River, New York 10965, United States., Sakata S; Pfizer Research & Development, La Jolla, California 92121, United States., Sammons MF; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Sathish JG; Pfizer Research & Development, Pearl River, New York 10965, United States., Sharma R; Pfizer Research & Development, Groton, Connecticut 06340, United States., Steppan CM; Pfizer Research & Development, Groton, Connecticut 06340, United States., Tuttle JB; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Verhoest PR; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Wei L; Pfizer Research & Development, Groton, Connecticut 06340, United States., Yang Q; Pfizer Research & Development, Cambridge, Massachusetts 02139, United States., Yurgelonis I; Pfizer Research & Development, Pearl River, New York 10965, United States., Zhu Y; Pfizer Research & Development, Pearl River, New York 10965, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 13550-13571. Date of Electronic Publication: 2024 Apr 30.
DOI:	10.1021/acs.jmedchem.3c02469
Abstrakt:	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.
Databáze:	MEDLINE
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