Structure-Atropisomer Stability Relationship in Selective MCL-1 Inhibitors

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Atropisomerism is increasingly important in drug candidates due to complex protein targets.
• Predicting atropisomer interconversion rates is vital for drug developability, requiring rates to be fast or very slow at ambient temperature.

Purpose of the Study:

• To investigate how structural features influence the interconversion of atropisomers in selective MCL-1 inhibitors.
• To establish a correlation between structural modifications and atropisomer stability.
• To enhance the predictability of atropisomer isomerization rates.

Main Methods:

• Synthesis and stability assessment of selective MCL-1 inhibitors.
• Nuclear Magnetic Resonance (NMR) kinetics studies at variable temperatures.
• Quantum chemical calculations to assess the isomerization process and rotational barriers.

Main Results:

• Experimental and theoretical studies showed good agreement in predicting atropisomer isomerization at ambient temperature.
• Measured rotational barriers for specific compounds aligned well with predicted values.
• Identified key structural features impacting atropisomer stability and interconversion.

Conclusions:

• A deeper understanding of structure-isomerization relationships was achieved for MCL-1 inhibitors.
• The findings enable more efficient optimization of atropisomerism in drug design.
• Improved predictability of atropisomer behavior facilitates the development of viable drug candidates.