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Structure-Atropisomer Stability Relationship in Selective MCL-1 Inhibitors.

Szabolcs Sipos¹, Barbara Balazs¹, Tamas Gati¹

¹Servier Research Institute of Medicinal Chemistry, Zahony u. 7., 1031, Budapest, Hungary.

|February 3, 2025

Summary

Understanding atropisomer interconversion is crucial for drug development. This study links structural features to isomerization rates in MCL-1 inhibitors, improving predictability for drug candidates.

Keywords:

NMR spectroscopy activation barrier atropisomer isomerization quantumchemical calculations

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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.