A research program to discover solubilizing prodrugs of the HCV NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug moiety is attached to a benzimidazole nitrogen atom via an oxymethyl linkage to allow for rapid and complete release of the drug for absorption following phosphate removal by intestinal alkaline phosphatase. These prodrugs have good hydrolytic stability properties and improved solubility compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5). TML prodrug 9 provided superior in vivo performance, delivering high plasma concentrations of PIB in PK studies conducted in mice, dogs, and monkeys. The improved dissolution properties of these phosphate prodrugs provide them the potential to simplify drug dosage forms for PIB-containing HCV therapy.

中文翻译：

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提高 HCV NS5A 抑制剂 Pibrentasvir (ABT-530) 溶解度的前药策略。

一项发现 HCV NS5A 抑制剂 pibrentasvir (PIB) 的增溶前药的研究计划确定了磷酸甲基类似物2和三甲基锁 (TML) 前药9。前药部分通过羟甲基键连接到苯并咪唑氮原子上，以允许药物在肠碱性磷酸酶去除磷酸盐后快速和完全释放以供吸收。与 PIB 相比，这些前药在水性缓冲液 (pH 7) 和 FESSIF (pH 5) 中均具有良好的水解稳定性和更高的溶解度。TML前药9提供卓越的体内性能，在小鼠、狗和猴子进行的 PK 研究中提供高血浆浓度的 PIB。这些磷酸盐前药改进的溶出特性为它们提供了简化用于含 PIB 的 HCV 治疗的药物剂型的潜力。