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核心技术专利：CN118964589B侵权必究
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一种用于治疗 COVID-19 的第二代口服 SARS-CoV-2 主蛋白酶抑制剂临床候选药物。

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

机构信息

Pfizer Research & Development, Cambridge, Massachusetts 02139, United States.

Pfizer Research & Development, Groton, Connecticut 06340, United States.

出版信息

J Med Chem. 2024 Aug 22;67(16):13550-13571. doi: 10.1021/acs.jmedchem.3c02469. Epub 2024 Apr 30.

DOI:10.1021/acs.jmedchem.3c02469
PMID:38687966
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11345836/
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 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 pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. 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.

摘要

尽管疫苗和抗病毒疗法（如 Paxlovid）的研发和审批创下了纪录，但 2022 年冠状病毒病（COVID-19）仍是全球第四大死亡原因，也是美国第三大死亡原因。在此，我们报告了 PF-07817883 的发现和特性，这是一种第二代、口服生物可利用的 SARS-CoV-2 主要蛋白酶抑制剂，与 Paxlovid 中利托那韦增强疗法的抗病毒成分奈玛特韦相比，其代谢稳定性得到了改善。我们展示了 PF-07817883 对泛人类冠状病毒的抗病毒活性和非靶点选择性特征。PF-07817883 在相当于奈玛特韦的血浆浓度下，在 SARS-CoV-2 小鼠适应模型中也显示出口服疗效。在人类基质中的临床前药代动力学和代谢研究表明，PF-07817883 在人体中的口服药代动力学相对于奈玛特韦有所改善。针对主要的人类药物代谢酶/转运体的抑制/诱导研究表明，PF-07817883 单独使用时药物相互作用的潜在风险较低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/12ece6a1ad8b/jm3c02469_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/29ae366e20b1/jm3c02469_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/a654fab99f2d/jm3c02469_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/2f815fb4080b/jm3c02469_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/3b2a79b93d92/jm3c02469_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/a29f2f033a93/jm3c02469_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/9ea6207bee19/jm3c02469_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/62d13b44f0a0/jm3c02469_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/e621d97e4a53/jm3c02469_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/12ece6a1ad8b/jm3c02469_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/29ae366e20b1/jm3c02469_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/a654fab99f2d/jm3c02469_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/2f815fb4080b/jm3c02469_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/3b2a79b93d92/jm3c02469_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/a29f2f033a93/jm3c02469_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/9ea6207bee19/jm3c02469_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/62d13b44f0a0/jm3c02469_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/e621d97e4a53/jm3c02469_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a73a/11345836/12ece6a1ad8b/jm3c02469_0009.jpg

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本文引用的文献

[1]
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Nat Commun. 2023-10-13

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N Engl J Med. 2022-4-14

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