Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors,Journal of Medicinal Chemistry

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Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-15 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00617
Johanna Huchting _{1,

2} , Evelien Vanderlinden ₂ , Matthias Winkler ₁ , Hiba Nasser ₁ , Lieve Naesens ₂ , Chris Meier ₁

Affiliation

We here disclose chemical synthesis of ribonucleoside 5′-monophosphate (RMP), -diphosphate (RDP), and -triphosphate (RTP) and cycloSal-, DiPPro-, and TriPPPro nucleotide prodrugs of the antiviral pseudobase T-1105. Moreover, we include one nucleoside diphosphate prodrug of the chemically less stable T-705. We demonstrate efficient T-1105-RDP and -RTP release from the DiPPro and TriPPPro compounds by esterase activation. Using crude enzyme extracts, we saw rapid phosphorylation of T-1105-RDP into T-1105-RTP. In sharp contrast, phosphorylation of T-1105-RMP was not seen, indicating a yet unrecognized bottleneck in T-1105’s metabolic activation. Accordingly, DiPPro and TriPPPro compounds displayed improved cell culture activity against influenza A and B virus, which they retained in a mutant cell line incapable of activating the nucleobase parent. T-1105-RTP had a strong inhibitory effect against isolated influenza polymerase, and DiPPro-T-1105-RDP showed 4-fold higher potency in suppressing one-cycle viral RNA synthesis versus T-1105. Hence, our T-1105-RDP and -RTP prodrugs improve antiviral potency and achieve efficient metabolic bypass.

中文翻译：

羟吡嗪羧酰胺假碱基T-705及其去氟类似物T-1105的磷酸核糖基化形式的前药作为强效流感病毒抑制剂

我们在这里公开了抗病毒假碱基T-1105的核糖核苷5'-单磷酸酯（RMP），-二磷酸酯（RDP）和-三磷酸酯（RTP）和环Sal-，Di PP ro-和Tri PPP ro核苷酸前药的化学合成。。此外，我们包括一种化学稳定性较差的T-705核苷二磷酸前药。我们展示了有效的T-1105-RDP和-RTP通过酯酶激活从Di PP ro和Tri PPP ro化合物中释放出来。使用粗酶提取物，我们看到T-1105-RDP迅速磷酸化为T-1105-RTP。与之形成鲜明对比的是，未观察到T-1105-RMP的磷酸化，这表明T-1105的代谢活化仍未识别出瓶颈。因此，Di PP ro和TriPPP ro化合物显示出针对甲型和乙型流感病毒的改善的细胞培养活性，它们保留在无法激活核碱基亲本的突变细胞系中。T-1105-RTP对分离的流感病毒聚合酶具有很强的抑制作用，而Di PP ro-T-1105-RDP在抑制一周期病毒RNA合成方面的功效是T-1105的4倍。因此，我们的T-1105-RDP和-RTP前药可提高抗病毒效力并实现有效的代谢旁路。

更新日期：2018-06-15

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