Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility

Masao Ohashi, Takuji Oyama, Endy Widya Putranto, Tsuyoshi Waku, Hiromi Nobusada, Ken Kataoka, Kenji Matsuno, Masakazu Yashiro, Kosuke Morikawa, Nam Ho Huh, Hiroyuki Miyachi

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.

Original languageEnglish
Pages (from-to)2319-2332
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number8
DOIs
Publication statusPublished - Apr 15 2013

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PPAR gamma
Solubility
Ligands
Acids
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Stomach Neoplasms
Cells
X-Rays
Cell Line
X rays
Water

Keywords

  • Human peroxisome proliferator-activated receptor
  • Partial agonist
  • PPAR gamma
  • Structural biology

ASJC Scopus subject areas

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

Cite this

Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility. / Ohashi, Masao; Oyama, Takuji; Putranto, Endy Widya; Waku, Tsuyoshi; Nobusada, Hiromi; Kataoka, Ken; Matsuno, Kenji; Yashiro, Masakazu; Morikawa, Kosuke; Huh, Nam Ho; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 8, 15.04.2013, p. 2319-2332.

Research output: Contribution to journalArticle

Ohashi, M, Oyama, T, Putranto, EW, Waku, T, Nobusada, H, Kataoka, K, Matsuno, K, Yashiro, M, Morikawa, K, Huh, NH & Miyachi, H 2013, 'Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility', Bioorganic and Medicinal Chemistry, vol. 21, no. 8, pp. 2319-2332. https://doi.org/10.1016/j.bmc.2013.02.003
Ohashi, Masao ; Oyama, Takuji ; Putranto, Endy Widya ; Waku, Tsuyoshi ; Nobusada, Hiromi ; Kataoka, Ken ; Matsuno, Kenji ; Yashiro, Masakazu ; Morikawa, Kosuke ; Huh, Nam Ho ; Miyachi, Hiroyuki. / Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 8. pp. 2319-2332.
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