Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry

Jun Ichi Kasuga, Minoru Ishikawa, Mitsuhiro Yonehara, Makoto Makishima, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 (EC50: 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 (EC50: 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.

Original languageEnglish
Pages (from-to)7164-7173
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number20
DOIs
Publication statusPublished - Oct 15 2010

Fingerprint

Peroxisome Proliferator-Activated Receptors
Solubility
Acids
Water
Buffers
Phosphates
Dihedral angle
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Crystal structure
Binding Sites
X-Rays
Ligands
X rays
Crystals
Molecules

Keywords

  • Aqueous solubility
  • Molecular design
  • Nuclear receptor
  • PPAR agonist

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry. / Kasuga, Jun Ichi; Ishikawa, Minoru; Yonehara, Mitsuhiro; Makishima, Makoto; Hashimoto, Yuichi; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 20, 15.10.2010, p. 7164-7173.

Research output: Contribution to journalArticle

Kasuga, Jun Ichi ; Ishikawa, Minoru ; Yonehara, Mitsuhiro ; Makishima, Makoto ; Hashimoto, Yuichi ; Miyachi, Hiroyuki. / Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 20. pp. 7164-7173.
@article{57a2fbc9ccbd4f43aea677d772504e19,
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 (EC50: 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 (EC50: 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.",
keywords = "Aqueous solubility, Molecular design, Nuclear receptor, PPAR agonist",
author = "Kasuga, {Jun Ichi} and Minoru Ishikawa and Mitsuhiro Yonehara and Makoto Makishima and Yuichi Hashimoto and Hiroyuki Miyachi",
year = "2010",
month = "10",
day = "15",
doi = "10.1016/j.bmc.2010.08.041",
language = "English",
volume = "18",
pages = "7164--7173",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "20",

}

TY - JOUR

T1 - Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry

AU - Kasuga, Jun Ichi

AU - Ishikawa, Minoru

AU - Yonehara, Mitsuhiro

AU - Makishima, Makoto

AU - Hashimoto, Yuichi

AU - Miyachi, Hiroyuki

PY - 2010/10/15

Y1 - 2010/10/15

N2 - 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 (EC50: 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 (EC50: 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.

AB - 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 (EC50: 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 (EC50: 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.

KW - Aqueous solubility

KW - Molecular design

KW - Nuclear receptor

KW - PPAR agonist

UR - http://www.scopus.com/inward/record.url?scp=77957574845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957574845&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2010.08.041

DO - 10.1016/j.bmc.2010.08.041

M3 - Article

C2 - 20843696

AN - SCOPUS:77957574845

VL - 18

SP - 7164

EP - 7173

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 20

ER -