Hydrogen/Deuterium Exchange for Chiral Stability Assessment in Acidic Methine-Containing Compounds.

ABSTRACT: Acidic methine-containing compounds are prone to racemization driven by keto-enol tautomerization, which can lead to products with distinct pharmacological and toxicological properties. Glutarimide, a core structural component of cereblon binders, and thiazolidinediones, a class of antidiabetic agents, are particularly susceptible to this instability. In this study, we developed an H/D exchange method to investigate the racemization or epimerization kinetics of 28 compounds, including 3 thiazolidinediones, as well as 13 molecular glues and 12 proteolysis targeting chimeras (PROTACs), both containing the glutarimide scaffold. In phosphate buffer (0.1 M, D₂O, pD 7.8) at 37 °C, the racemization half-lives of glutarimide-based molecular glues ranged from 3.0 to 7.3 h, while thiazoli

SUBMITTER: Yu ZJ 

PROVIDER: S-EPMC12676523 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature