Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure

Michiaki Hiramatsu, Yuki Ichikawa, Shusuke Tomoshige, Makoto Makishima, Atsuya Muranaka, Masanobu Uchiyama, Takao Yamaguchi, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (log P) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes.

Original languageEnglish
Pages (from-to)2210-2217
Number of pages8
JournalChemistry - An Asian Journal
Volume11
Issue number15
DOIs
Publication statusPublished - 2016 Aug 5
Externally publishedYes

Keywords

  • aqueous solubility
  • drug design
  • intermolecular interaction
  • medicinal chemistry
  • melting point

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

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