Aqueous solubility is essential for drug candidates, and improvement of the aqueous solubility of bioactive compounds is a major issue for medicinal chemists. The strategy of introducing hydrophilic group(s) into molecules is generally used for this purpose, but is not universally effective. We proposed an alternative strategy for improving aqueous solubility, that is, modification of bicyclic molecules in ways that would disrupt molecular planarity by increasing the dihedral angle or that would disrupt the molecular symmetry. Such planarity- or symmetry-disruption has the effect of decreasing the efficiency of crystal packing, which in turn results in an increase of aqueous solubility. Improvement of aqueous solubility by 350-fold was achieved in one example. Furthermore, to clarify the mechanisms of improvement of aqueous solubility, we examined the changes in physicochemical properties of the compounds. Possible advantages of this approach are discussed.[1] J. Med. Chem. 2011 , 54, 1539-1554.

Improvement in solubility of bicyclic molecules focusing on dihedral angle and symmetry

243rd National Meeting (2012)

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