title: Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry.
abstract: To elucidate the molecular basis of peroxisome proliferator-activated receptor (PPAR) δ partial agonism, X-ray crystal structures of complexes of the PPARδ ligand-binding site with partial agonists are required. Unfortunately, reported PPARδ partial agonists, biphenylcarboxylic acids 1 and 2, possess insufficient aqueous solubility to allow such crystals to be obtained. To improve the aqueous solubility of 1 and 2, substituents were introduced at the 2-position of the biaryl moiety, focusing on disruption of molecular planarity and symmetry. All 2-substituted biphenyl analogs examined showed more potent PPARδ agonistic activity with greater aqueous solubility than 1 or 2. Among these biphenyls, 25 showed potent and selective PPARδ partial agonistic activity (EC(50): 5.7 nM), with adequate solubility in phosphate buffer (0.022 mg/mL). The 2-substituted pyridyl analog 27 showed weaker PPARδ partial agonistic activity (EC(50): 76 nM) with excellent solubility in phosphate buffer (2.7 mg/mL; at least 2700 times more soluble than 2). Our results indicate that two strategies to improve aqueous solubility, that is, introduction of substituent(s) to modify the dihedral angle and to disrupt molecular symmetry, may be generally applicable to bicyclic molecules. Combination of these approaches with the traditional approach of reducing the molecular hydrophobicity may be particularly effective.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kasuga
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yonehara
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D047494:PPAR delta; D014867:Water