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

Atropisomersm is an emerging feature in recent drug candidates due to the increasing complexity of the targeted protein surfaces. The developability of the drug candidates requires that their atropisomer interconversion is either fast or very slow at ambient temperature therefore the understanding and predictability of the isomerization rate is of great importance. Through a series of selective MCL-1 inhibitors we studied how structural features influence the interconversion of atropisomers. Besides basic observations such as stability in solution, we also carried out NMR kinetics at varying temperatures and a quantum chemical assessment of the isomerization process. The results of our theoretical studies and experimental investigations matched nicely when it came to predicting the presence or absence of isomerization at ambient temperature. For certain compounds we also measured the rotational barrier that fitted nicely the predicted values. The better understanding of how structural elements impact atropisomer stability enables the more efficient optimization of this important feature.