Atropisomerism in Drug Discovery


Following up on their earlier mini-review, the authors of this recent paper outline their work at Boehringer Ingelheim on developing methodology and strategies for dealing with the issue of atropisomerism in drug discovery.  The authors highlight the fact that, whilst the regulatory authorities provide no direct guidance on how to deal with time-dependent chirality, there is clearly a need to identify compounds which have atropisomeric chirality as early on as possible in order to move away from or to manage the progression of such compounds effectively.

The authors outline a practical and qualitative computational approach to predicting the energy barriers to axial rotation in molecules with the potential to form atropisomers.  Their method showed good agreement between calculated and experimental values even in non-obvious cases such as that shown below (an example from an AstraZeneca publication).

Calculated rotational energy barriers and incidence of atropisomerism for two compounds reported by AstraZeneca

They then go on to define a classification system, based on their computational method, in which compounds are placed into one of three groups.  Each group defines the likely atropisomeric status of a compound and the most appropriate development strategy.

i.e.:

  • Class 1 compounds (ΔErot < ~20 kcal/mol).  Fast axial rotation rates.  No atropisomerism.  Developed as purified, single compounds.
  • Class 2 compounds (~20 kcal/mol ≤ ΔErot ≤ ~30 kcal/mol).  Delayed axial interconversion (half life in the range of minutes to months).  Most challenging class to develop. Best developed as stereoisomeric mixtures if the ratio of isomers is maintained during the in vivo phase and the toxicological profile is acceptable. Alternatively, if identified early enough, steps can be taken to move away from compounds of this class by increasing rotation rates or by freezing out the rotation (i.e. moving into Class 1 or Class 3 respectively) or eliminating the chiral axis (e.g. by symmetrization).
  • Class 3 compounds (ΔErot >> ~30 kcal/mol).  Very slow torsion rotation rates (half-life ~ years).  Optical isomers can be isolated and developed in the same was as ‘classical’ stereoisomers deriving from chiral centers.

The paper finishes with an interesting application of their method to a database of launched and late-phase compounds and they discuss some of the findings of that exercise.

This is a must read for any medicinal chemist.  The issue of atropisomerism is often overlooked,  particularly earlier on in the hit-to-lead and lead-optimisation processes, and this article describes a clear strategy for highlighting and dealing with this form of chirality.

(Note: The authors do point out that their method doesn’t apply to atropisomerism resulting from limited inversion of medium-sized rings.)

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