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

Area of Science:

• Medicinal Chemistry
• Chemical Kinetics
• Drug Discovery

Background:

• Acidic methine-containing compounds, including glutarimide and thiazolidinedione scaffolds, are prone to racemization via keto-enol tautomerization.
• This instability can alter pharmacological and toxicological profiles of drug candidates.

Purpose of the Study:

• To develop and apply an H/D exchange method for assessing racemization and epimerization kinetics.
• To evaluate the chiral stability of glutarimide-based molecular glues, proteolysis targeting chimeras (PROTACs), and thiazolidinediones.

Main Methods:

• Utilized H/D exchange in D2O phosphate buffer (pD 7.8) at 37°C to measure racemization half-lives.
• Corroborated H/D exchange rates with chiral supercritical fluid chromatography.
• Investigated the impact of deuteration (reverse D/H exchange) on chiral stability via kinetic isotope effects.

Main Results:

• Glutarimide-based molecular glues had racemization half-lives of 3.0–7.3 h; thiazolidinediones were faster (0.8–1.0 h).
• Methine-deuterated compounds showed 3.6- to 8.5-fold improved chiral stability.
• PROTACs generally exhibited greater chiral stability than molecular glues; human serum albumin had variable effects.

Conclusions:

• The H/D exchange method provides a robust and streamlined approach for evaluating chiral stability.
• Deuteration is a viable strategy to enhance the chiral stability of therapeutic agents.
• Distinct chiral behaviors were observed between PROTACs and molecular glues, warranting further investigation into PROTAC conformations and stability.