Main protease (Mpro) is a superior target for anti-SARS-COV-2 drugs. PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into the active metabolite PF-00835231 by alkaline phosphatase (ALP) and then suppresses SARS-CoV-2 replication by inhibiting Mpro. PF-07304814 increased the bioavailability of PF-00835231 by enhancing plasma protein binding (PPB). P-glycoprotein (P-gp) inhibitors and cytochrome P450 3A (CYP3A) inhibitors increased the efficacy of PF-00835231 by suppressing its efflux from target cells and metabolism, respectively. The life cycle of SARS-CoV-2 is approximately 4 h. The mechanisms and efficacy outcomes of PF-00835231 occur simultaneously. PF-00835231 can inhibit not only cell infection (such as Vero E6, 293T, Huh-7.5, HeLa+angiotensin-converting enzyme 2 (ACE2), A549+ACE2, and MRC-5) but also the human respiratory epithelial organ model and animal model infection. PF-07304814 exhibits a short terminal elimination half-life and is cleared primarily through renal elimination. There were no significant adverse effects of PF-07304814 administration in rats. Therefore, PF-07304814 exhibits good tolerability, pharmacology, pharmacodynamics, pharmacokinetics, and safety in preclinical trials. However, the Phase 1 data of PF-07304814 were not released. The Phase 2/3 trial of PF-07304814 was also suspended. Interestingly, the antiviral activities of PF-00835231 derivatives (compounds 5–22) are higher than, similar to, or slightly weaker than those of PF-00835231. In particular, compound 22 exhibited the highest potency and had good safety and stability. However, the low solubility of compound 22 limits its clinical application. Prodrugs, nanotechnology and salt form drugs may solve this problem. In this review, we focus on the preclinical data of PF-07304814 and its active metabolite derivatives to hopefully provide knowledge for researchers to study SARS-CoV-2 infection.

中文翻译：

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PF-07304814及其活性代谢衍生物抗SARS-CoV-2感染的临床前数据回顾

主要蛋白酶 (M临) 是抗 SARS-COV-2 药物的上佳靶标。PF-07304814 是 PF-00835231 的磷酸酯前体药物，通过碱性磷酸酶 (ALP) 快速代谢为活性代谢物 PF-00835231，然后通过抑制 M 来抑制 SARS-CoV-2 复制临. PF-07304814 通过增强血浆蛋白结合 (PPB) 提高 PF-00835231 的生物利用度。P-糖蛋白 (P-gp) 抑制剂和细胞色素 P450 3A (CYP3A) 抑制剂分别通过抑制其从靶细胞流出和代谢来提高 PF-00835231 的功效。SARS-CoV-2 的生命周期约为 4 小时。PF-00835231 的机制和疗效结果同时发生。PF-00835231不仅可以抑制细胞感染（如Vero E6、293T、Huh-7.5、HeLa+血管紧张素转换酶 2 (ACE2), A549+ACE2, 和 MRC-5) 以及人类呼吸道上皮器官模型和动物模型感染。PF-07304814 表现出较短的终末消除半衰期，主要通过肾脏消除清除。在大鼠中施用 PF-07304814 没有明显的副作用。因此，PF-07304814在临床前试验中表现出良好的耐受性、药理学、药效学、药代动力学和安全性。但是，PF-07304814的Phase 1数据并未公布。PF-07304814的2/3期试验也被暂停。有趣的是，PF-00835231 衍生物（化合物 5-22）的抗病毒活性高于、类似于或略低于 PF-00835231。特别是化合物22表现出最高的效价并且具有良好的安全性和稳定性。然而，化合物22的低溶解度限制了其临床应用。前药、纳米技术和盐形式的药物可能会解决这个问题。在这篇综述中，我们重点关注 PF-07304814 及其活性代谢产物衍生物的临床前数据，希望为研究人员研究 SARS-CoV-2 感染提供知识。