title: Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure.
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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiramatsu
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Tomoshige
authors.affiliation: Nihon University, School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: Elements Chemistry Laboratory and, Advanced Elements Chemistry Research Team, Center for Sustainable Resource Science (CSRS), RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
authors.forename: Atsuya
authors.initials: A
authors.lastname: Muranaka
authors.affiliation: Elements Chemistry Laboratory and, Advanced Elements Chemistry Research Team, Center for Sustainable Resource Science (CSRS), RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.|Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Uchiyama
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan. m-ishikawa@iam.u-tokyo.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013816:Thermodynamics; D044366:Transition Temperature; D014867:Water / Q000737:chemistry*
chemical_list: D001565:Benzoates; D018168:Receptors, Retinoic Acid; D014867:Water
keywords: aqueous solubility; drug design; intermolecular interaction; medicinal chemistry; melting point