Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) δ-selective agonists

Jun ichi Kasuga, Izumi Nakagome, Atsushi Aoyama, Kumiko Sako, Michiyasu Ishizawa, Michitaka Ogura, Makoto Makishima, Shuichi Hirono, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) δ-selective agonists, based on our previously discovered potent human PPARα/δ dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARδ transactivation activity and highest PPARδ selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARδ transactivation activity, comparable with or somewhat superior to that of the known PPARδ-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARδ function, but also as a candidate drug for the treatment of metabolic syndrome.

Original languageEnglish
Pages (from-to)5177-5190
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number15
DOIs
Publication statusPublished - Aug 1 2007

Keywords

  • Metabolic syndrome
  • PPAR
  • PPARδ
  • PPARδ-selective agonist

ASJC Scopus subject areas

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

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    Kasuga, J. I., Nakagome, I., Aoyama, A., Sako, K., Ishizawa, M., Ogura, M., Makishima, M., Hirono, S., Hashimoto, Y., & Miyachi, H. (2007). Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) δ-selective agonists. Bioorganic and Medicinal Chemistry, 15(15), 5177-5190. https://doi.org/10.1016/j.bmc.2007.05.023