SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail

Jun ichi Kasuga, Daisuke Yamasaki, Kiyoshi Ogura, Motomu Shimizu, Mayumi Sato, Makoto Makishima, Takefumi Doi, Yuichi Hashimoto, Hiroyuki Miyachi

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27 Citations (Scopus)

Abstract

3-(4-Alkoxyphenyl)propanoic acid derivatives were prepared as candidate peroxisome proliferator-activated receptor (PPAR) α/δ/γ pan agonists, based on our previous SAR studies directed toward the development of subtype-selective PPAR agonists. Those studies indicated that the steric bulkiness of substituents introduced at the distal benzene ring had an important influence on PPAR activity. The finding that a 4-adamantyl derivative exhibited not only PPARα/δ activity but also significant PPARγ activity prompted us to search for structurally novel phenylpropanoic acid derivatives with more potent adipocyte differentiation activity than the well-known PPARγ agonist, rosiglitazone, as well as well-balanced PPARα and PPARδ agonistic activities. A representative phenylpropanoic acid derivative (12) bearing a 4-adamantylphenyl substituent proved to be a well-balanced PPAR-pan agonist with activities to regulate the expression of genes involved in lipid and glucose homeostasis, and should be useful as a candidate drug for the treatment of altered PPAR function.

Original languageEnglish
Pages (from-to)1110-1115
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number3
DOIs
Publication statusPublished - Feb 1 2008

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Keywords

  • Metabolic syndrome
  • PPAR
  • PPAR-pan agonist
  • Phenylpropanoic acid

ASJC Scopus subject areas

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

Cite this

Kasuga, J. I., Yamasaki, D., Ogura, K., Shimizu, M., Sato, M., Makishima, M., Doi, T., Hashimoto, Y., & Miyachi, H. (2008). SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail. Bioorganic and Medicinal Chemistry Letters, 18(3), 1110-1115. https://doi.org/10.1016/j.bmcl.2007.12.001