Atropisomerism - A Neglected Way to Escape Out of Solubility Flatlands

Low solubility of drugs represents a major challenge during research and development. Ways to overcome this are either focused on formulation development or optimization of the molecular structure of the drug. The latter is not only governed by the constitution of the molecule but also by its stereochemistry. Development of enantiomers in contrast to racemic mixtures has become the state of the art over the last decades as this leads to higher potency and selectivity. Thus, enantiopure drugs require lower doses compared to their racemates. Additionally, selecting one enantiomer also leads to improved solubility of the drug compared to its racemic compound. While this effect is well known for enantiomers and racemic compounds where chirality is introduced via a chiral central atom, here we describe the first case where improved solubility is realized by selecting an axially chiral atropisomer.