Monophosphate prodrug analogs of 2′-deoxy-2′-fluoro-2′-C-methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2′-deoxy-2′-fluoro-2′-C-methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate, prodrug 17, demonstrating well-balanced anti-dengue virus cellular activity and in vitro stability profiles. We further determined the PBMC concentration of active triphosphate needed to inhibit virus replication by 50% (TP₅₀). Compound 17 was assessed in an AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reductions at 100 and 300 mg/kg twice a day (BID), respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs exceeded the TP₅₀ value, demonstrating TP₅₀ as the target exposure for efficacy. In dogs, oral administration of compound 17 resulted in high PBMC triphosphate levels, exceeding the TP₅₀ at 10 mg/kg. Unfortunately, 2-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that “no observed adverse effect level” (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of compound 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue virus infection.

中文翻译：

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2'-脱氧-2'-氟-2'-C-甲基鸟苷的环状磷酸氨基磷酸前药，用于治疗登革热感染。

据报道，2'-脱氧-2'-氟-2'- C-甲基鸟苷的单磷酸盐前药类似物是丙型肝炎病毒（HCV）RNA依赖性RNA聚合酶的有效抑制剂。这些前药在细胞分析中也显示出有效的抗登革热病毒活性，尽管其前药部分被设计为在肝脏中产生高水平的三磷酸。由于外周血单核细胞（PBMC）是登革热病毒的主要靶标，因此设计了不同的前药部分，可将2'-脱氧-2'-氟-2'- C-甲基鸟苷一磷酸前药及其相应的三磷酸有效地递送至PBMC中。口服。我们确定了一种环状氨基磷酸酯，前药17，证明了抗登革热病毒细胞活性和体外平衡良好稳定性概况。我们进一步确定了抑制病毒复制50％（TP ₅₀）所需的活性三磷酸PBMC浓度。在AG129小鼠模型中评估了化合物17，并证明每天两次分别以100和300 mg / kg的剂量（BID）减少1.6和2.2对数的病毒血症。在BID为100 mg / kg时，PBMC中三磷酸的终浓度超过了TP ₅₀值，表明TP ₅₀是功效的目标暴露量。在狗中，口服化合物17导致PBMC三磷酸水平升高，超过TP ₅₀10 mg / kg。不幸的是，以30、100和300 mg / kg / day进行的为期2周的狗毒性研究表明，由于肺部炎症和出血，无法达到“未观察到的不良反应水平”（NOAEL）。临床前的安全性结果中止了化合物17的进一步开发。尽管如此，目前的工作证明了可以开发有效的单磷酸核苷前药这一概念，用于治疗登革热病毒感染的潜在可能性。