Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure |
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| Authors: | Michiaki Hiramatsu Yuki Ichikawa Dr. Shusuke Tomoshige Prof. Makoto Makishima Dr. Atsuya Muranaka Prof. Masanobu Uchiyama Dr. Takao Yamaguchi Prof. Yuichi Hashimoto Dr. Minoru Ishikawa |
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| Affiliation: | 1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan;2. Nihon University, School of Medicine, Itabashi-ku, Tokyo, Japan;3. Elements Chemistry Laboratory and, Advanced Elements Chemistry Research Team, Center for Sustainable Resource Science (CSRS), RIKEN, Wako-shi, Saitama, Japan;4. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan |
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| 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. |
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| Keywords: | aqueous solubility drug design intermolecular interaction medicinal chemistry melting point |
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