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Review
. 2018 Feb;10(4):409-422.
doi: 10.4155/fmc-2017-0152. Epub 2018 Jan 30.

Atropisomerism in medicinal chemistry: challenges and opportunities

Sean T Toenjes  1 , Jeffrey L Gustafson  1
Affiliations
Review

Atropisomerism in medicinal chemistry: challenges and opportunities

Sean T Toenjes et al. Future Med Chem. 2018 Feb.

Abstract

Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. There are several examples of stable atropisomeric US FDA-approved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities. Rapidly interconverting atropisomerism is even more prevalent, and while such compounds are typically considered achiral, they bind their protein targets in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities. It has been recently demonstrated that various properties of an interconverting atropisomer can be modulated through the synthesis of atropisomer stable and pure analogs. Herein we discuss examples of atropisomerism in drug discovery as well as challenges and opportunities moving forward.

Keywords: atropisomer; chirality; drug discovery; kinase inhibitor; target selectivity.

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Conflict of interest statement

Financial & competing interests disclosure

JL Gustafson had an NIH grant funded for the atropisomer medicinal chemistry projects. ST Toenjes was bought out from teaching responsibilities with some of these funds and received salary support as well. The Grant ID is R35GM124637. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Atropisomerism is a type of chirality that is potentially present in many common scaffolds in drug discovery.
Atropisomers can exist as either stable isolable enantiomers or rapidly interconverting racemizing mixtures.
<b>Figure 2.</b>
Figure 2.. Barrier to rotation energy diagram.
M06–2X/6–31+G(d)//RB3LYP/6–31G(d); RB3LYP/6–31G(d) thermal corrections.
<b>Figure 3.</b>
Figure 3.. US FDA-approved small-molecule drugs that are atropisomerically stable.
<b>Figure 4.</b>
Figure 4.. Atropisomeric stable compounds from the medicinal chemical literature.
<b>Figure 5.</b>
Figure 5.. Racemizing atropisomeric and proatropisomeric FDA-approved drugs.
(A) US FDA-approved class one atropisomers. (B) FDA-approved proatropisomeric compounds.
<b>Figure 6.</b>
Figure 6.. Demonstration that control of atropisomer conformation can modulate the selectivity of a promiscuous small molecule.
<b>Figure 7.</b>
Figure 7.. Example of a selective and potent stable atropisomeric inhibitor.
See this image and copyright information in PMC

References

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