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.

中文翻译：

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用于治疗 COVID-19 的第二代口服 SARS-CoV-2 主要蛋白酶抑制剂临床候选药物

尽管疫苗和 Paxlovid 等抗病毒疗法的发现、开发和批准取得了破纪录的进展，但 2019 年冠状病毒病 (COVID-19) 仍然是 2022 年世界第四大死因，在美国排名第三。报告了 PF-07817883 的发现和表征，PF-07817883 是第二代口服生物可利用的 SARS-CoV-2 主要蛋白酶抑制剂，与利托那韦增强疗法 Paxlovid 的抗病毒成分 nirmatrelvir 相比，其代谢稳定性得到改善。我们展示了PF-07817883 的体外泛人类冠状病毒抗病毒活性和脱靶选择性特征。 PF-07817883 还在小鼠适应的 SARS-CoV-2 模型中证明了口服疗效，其血浆浓度相当于 nirmatrelvir。人体基质的临床前体内药代动力学和代谢研究表明，相对于 nirmatrelvir，PF-07817883 在人体中的口服药代动力学有所改善。针对主要人类药物代谢酶/转运蛋白的体外抑制/诱导研究表明，单用 PF-07817883 时，药物间相互作用的可能性较低。