Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent

The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug–drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug’s exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and Cmax between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.

弱碱性TYK2抑制剂1的pH依赖性溶解度对其研发进程构成了风险，因为此类特性的药物已被证实会在人体内与抑酸剂发生药物相互作用（DDI）。在pH依赖性大鼠模型中，预先给予法莫替丁的大鼠体内受试物1的暴露量较对照组大鼠低2.4倍，这提示pH依赖性口服吸收会降低活性药物的全身暴露量，进而可能导致治疗剂量不足。为缓解该风险，研究团队探索了前药策略：通过合成增溶性前药，最终筛选得到先导前药3c，其稳定性与溶解度特性均达到可接受标准。在大鼠体内实验中，该前药消除了五肽胃泌素给药组与法莫替丁给药组之间药时曲线下面积（AUC）和峰浓度（Cmax）的显著差异，从而有效缓解了在与药物吸收相关的升高pH环境下，以及与法莫替丁发生药物相互作用时受损的药物吸收情况。此外，该前药在大鼠和猴中进行剂量递增给药时，可使受试物1实现剂量比例性的全身暴露。