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

Lingxuan Zhu; Wei Wang; Qingjiao Li; Hanqi Wang; Xinsheng Lei

doi:10.1016/j.bmc.2025.118064

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

Bioorg Med Chem. 2025 Jan 5:119:118064. doi: 10.1016/j.bmc.2025.118064. Online ahead of print.

Authors

Lingxuan Zhu¹, Wei Wang¹, Qingjiao Li², Hanqi Wang¹, Xinsheng Lei³

Affiliations

¹ School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.
² School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China. Electronic address: leixs@fudan.edu.cn.

PMID: 39793402
DOI: 10.1016/j.bmc.2025.118064

Abstract

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.

Keywords: IYS-15; Microsomal stability; Plasma stability; Prodrug derivatives; Thiol.