The Preorganization of Atropisomers to Increase Target Selectivity

Atropisomerism is a form of chirality that arises from differential substitution around a bond that renders the rotational isomers enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as either stable isolable enantiomers or rapidly racemizing atropisomeric mixtures. Many biologically active small molecules exist as rapidly interconverting atropisomers, however, only one of the possible atropisomers possesses the desired activity. The presence of the nonrelevant atropisomer via spontaneous racemization can result in off-target activities that can lead to side effects. We have hypothesized that preorganizing (locking) a freely interconverting atropisomeric axis in a promiscuous scaffold into the target relevant atropisomer can serve as a general strategy towards more selective small molecule inhibitors. This article outlines recent literature on atropisomerism in drug discovery as well as our recent efforts towards increasing the target selectivity of small molecule kinase inhibitors through ‘atropisomer preorganization’.