Probing into the plasma stability and microsomal stability of thiol-based prodrug derivatives: Using IYS-15, an HDAC inhibitor as the model thiol

Thiols have interesting bio-chemical properties and can be found in a number of approved drugs. However, some thiols exhibited poor plasma stability and microsomal stability, leading to poor in vivo activity and poor oral bio-availability, in spite of their potent activity in vitro. Prodrug is a classic strategy to improve drug pharmacokinetics. In this study, we designed and synthesized 25 prodrug derivatives of a potent thiol-based HDAC inhibitor, IYS-15, to explore the structure-plasma stability relationships and structure-microsomal stability relationships in these series. We also tried to identify the main metabolic enzymes participated in the metabolism of some representative thiol-based prodrug derivatives. This work thus presents a comparison between different prodrugs based on the same model thiol, giving insights into the stability profile of the synthesized prodrug derivatives in human plasma and human liver microsomes, and more importantly, might also provide structural guidance to medicinal chemists in the design of thiol-based prodrugs and other novel prodrugs with thiol-based linkers.