Prodrug Strategy\nto Address Impaired Oral Absorption\nof a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing\nAgent

The pH-dependent solubility of the weakly basic TYK2\ninhibitor <b>1</b> posed a risk to its advancement, given that\ndrugs with such\nprofiles have exhibited drug–drug interaction (DDI) with stomach\nacid-reducing agents in humans. In a rat model of pH dependence, preadministration\nof famotidine caused a 2.4-fold lower exposure of <b>1</b> when\ncompared to control rats, implying that pH-dependent oral absorption\ncan reduce the active drug’s exposure and translate to subtherapeutic\ntreatment. As part of risk mitigation, a prodrug strategy was explored\nby synthesizing solubility-enhancing prodrugs, resulting in the identification\nof lead prodrug <b>3c</b> with acceptable stability and solubility\nprofiles. In rats, the prodrug eliminated the significant difference\nin AUC and <i>C</i><sub>max</sub> between pentagastrin and\nfamotidine arms, thereby effectively mitigating the impaired drug\nabsorption at the elevated pH relevant for absorption and DDI with\nfamotidine. The prodrug also facilitated dose-proportional systemic\nexposure of <b>1</b> following dose escalation in rats and monkeys.