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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
rosiglitazone
Derivatives
Bearings (structural)
Acids
Propionates
Benzene
Adipocytes
Homeostasis
Genes
Lipids
Gene Expression
Glucose

Keywords

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

ASJC Scopus subject areas

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

Cite this

SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail. / Kasuga, Jun ichi; Yamasaki, Daisuke; Ogura, Kiyoshi; Shimizu, Motomu; Sato, Mayumi; Makishima, Makoto; Doi, Takefumi; Hashimoto, Yuichi; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 3, 01.02.2008, p. 1110-1115.

Research output: Contribution to journalArticle

Kasuga, JI, 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, vol. 18, no. 3, pp. 1110-1115. https://doi.org/10.1016/j.bmcl.2007.12.001
Kasuga, Jun ichi ; Yamasaki, Daisuke ; Ogura, Kiyoshi ; Shimizu, Motomu ; Sato, Mayumi ; Makishima, Makoto ; Doi, Takefumi ; Hashimoto, Yuichi ; Miyachi, Hiroyuki. / SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 3. pp. 1110-1115.
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