Drug candidates can be classified, according to the BCS system, into four groups on the basis of their permeability and aqueous solubility. Molecules with lower solubility tend to be more difficult to develop and are subject to closer scrutiny by regulatory bodies (e.g. FDA). Whilst formulation can address solubility deficits to an extent, designing clinical candidates with sufficient intrinsic solubility is generally preferred. The most widespread approach to improving solubility within a compound class relies on the introduction of hydrophilic groups in order to lower the log P (which generally correlates with aqueous solubility). However, this strategy is not always appropriate or possible and an alternative approach involves devising structural modifications which, by disrupting planarity and/or symmetry, lower crystal packing energies and reduce the energy barrier to dissolution in water.
The latter approach is the subject of a J.Med.Chem. perspective by authors from the University of Tokyo. The paper describes some of their own work in the area and also reviews relevant examples from the literature. The various examples are grouped according to the specific structural modification:
- Removal of aromaticity
- Increased dihedral angle/disruption of molecular symmetry (see example below)
- Introduction of substituents into benzylic position
- Twisting of fused rings
The examples presented in this paper clearly demonstrate the utility of this approach and the importance of considering these types of molecular modifications alongside the more classical introduction of polar, solubilizing groups.