Improvement in Aqueous Solubility of Bioactive Molecules by Decreasing Intermolecular Interaction

研究成果: Review article査読

抄録

Sufficient aqueous solubility is a key requirement for small molecular drug candidates, and improvement of the aqueous solubility of bioactive compounds is often a major issue for medicinal chemists. Decreasing the partition coefficient (Log P) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. On the other hand, the solubility of a solid solute in water is also dependent on the crystal packing of the solute suggesting the existence of another principle of solvation. We have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. In this review, we summarize the strategies for improving solubility, that is, modification of molecules in ways that would disrupt molecular planarity by increasing the dihedral angle, that would bend the molecular structure, that would disrupt molecular symmetry, or that introduce a non-flat substituent at the meta position of a benzene substructure. We showed that these strategies can increase the aqueous solubility of molecules even if their hydrophobicity is concomitantly increased. Furthermore, we found that disruption of intermolecular interaction resulted in better aqueous solubility than a decrease of hydrophobicity in some cases.

本文言語English
ページ(範囲)365-379
ページ数15
ジャーナルYakugaku zasshi : Journal of the Pharmaceutical Society of Japan
142
4
DOI
出版ステータスPublished - 2022

ASJC Scopus subject areas

  • 薬理学
  • 薬科学

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